Muscle time under tension during resistance exercise stimulates differential muscle protein sub-fractional synthetic responses in men.
We aimed to determine if the time that muscle is under loaded tension during low intensity resistance exercise affects the synthesis of specific muscle protein fractions or phosphorylation of anabolic signalling proteins. Eight men (24 ± 1 years (sem), BMI = 26.5 ± 1.0 kg m(-2)) performed three sets of unilateral knee extension exercise at 30% of one-repetition maximum strength involving concentric and eccentric actions that were 6 s in duration to failure (SLOW) or a work-matched bout that consisted of concentric and eccentric actions that were 1 s in duration (CTL). Participants ingested 20 g of whey protein immediately after exercise and again at 24 h recovery. Needle biopsies (vastus lateralis) were obtained while fasted at rest and after 6, 24 and 30 h post-exercise in the fed-state following a primed, constant infusion of l-[ring-(13)C(6)]phenylalanine. Myofibrillar protein synthetic rate was higher in the SLOW condition versus CTL after 24-30 h recovery (P < 0.001) and correlated to p70S6K phosphorylation (r = 0.42, P = 0.02). Exercise-induced rates of mitochondrial and sarcoplasmic protein synthesis were elevated by 114% and 77%, respectively, above rest at 0-6 h post-exercise only in the SLOW condition (both P < 0.05). Mitochondrial protein synthesis rates were elevated above rest during 24-30 h recovery in the SLOW (175%) and CTL (126%) conditions (both P < 0.05). Lastly, muscle PGC-1α expression was increased at 6 h post-exercise compared to rest with no difference between conditions (main effect for time, P < 0.001). These data show that greater muscle time under tension increased the acute amplitude of mitochondrial and sarcoplasmic protein synthesis and also resulted in a robust, but delayed stimulation of myofibrillar protein synthesis 24-30 h after resistance exercise.


The role of reported tobacco-specific media exposure on adult attitudes towards proposed policies to limit the portrayal of smoking in movies.
To assess the relative, independent contribution of reported tobacco-specific media exposure (pro-tobacco advertising, anti-tobacco advertising, and news coverage of tobacco issues) to US adults' support for policy efforts that aim to regulate the portrayal of smoking in movies. Using the American Legacy Foundation's 2003 American Smoking and Health Survey (ASHES-2), multivariable logistic regression was used to model the predicted probability that US adults support movie-specific tobacco control policies, by reported exposure to tobacco-specific media messages, controlling for smoking status, education, income, race/ethnicity, age, sex, knowledge of the negative effects of tobacco and state. Across most outcome variables under study, findings reveal that reported exposure to tobacco-specific media messages is associated with adult attitudes towards movie-specific policy measures. Most exposure to tobacco information in the media (with the exception of pro-tobacco advertising on the internet) contributes independently to the prediction of adult support for movie-specific policies. The direction of effect follows an expected pattern, with reported exposure to anti-tobacco advertising and news coverage of tobacco predicting supportive attitudes towards movie policies, and reported exposure to pro-tobacco advertising lessening support for some movie policies, though the medium of delivery makes a difference. Media campaigns to prevent tobacco use and exposure to secondhand smoke have had value beyond the intended impact of single-issue campaigns; exposure to anti-tobacco campaigns and public dialogue about the dangers of tobacco seem also to be associated with shaping perceptions of the social world related to norms about tobacco, and ideas about regulating the portrayal of smoking in movies.


Incorporating Affordability Concerns Within Cost-Effectiveness Analysis for Health Technology Assessment.
Recent policy developments and journal articles have emphasized a divergence: when interventions are found to be cost-effective but unaffordable. This apparent paradox reflects a conventional practice of cost-effectiveness analysis that does not properly evaluate the opportunity costs of an intervention that imposes non-marginal costs on the healthcare system. Taking the perspective of an exogenously resource constrained decision maker, this paper presents a framework by which concerns for affordability can be appropriately incorporated within cost-effectiveness analysis. A net benefit framework is proposed where health opportunity costs are estimated for each simulation iteration within each time period. The framework is applied to a hypothetical case study based on the recent experience of the English NHS with new hepatitis C drugs. Under the proposed framework, but not under conventional cost-effectiveness analysis, estimates of health opportunity costs differ between scenarios involving different profiles of budget impact even when their net present value, or expected value, are the same. The framework presented here reflects the importance of the scale of budget impacts along with their uncertainty distribution and time profile. In doing so it resolves issues with the conduct of conventional cost-effectiveness analysis where affordability concerns are not explicitly incorporated.


Importance of Nonhuman Primates as a Model System for Gene Therapy Development in Ophthalmology.
Gene therapy is a treatment concept that uses, in most cases, viral vectors to deliver a therapeutic transgene to target cells. Although the idea of gene therapy dates back over 50 years ago, due to the complexity of the treatment concept, it took until the last decade for the responsible agencies like FDA and EMA to recommend the first gene therapy products for clinical use. The development of these therapies relies on molecular engineering of specifically designed vectors and models to test the effectiveness and safety of the treatment. Despite an increasing effort to find effective surrogates, animal models are still irreplaceable in gene therapy development. Rodents are important for exploring pathways and disease mechanisms and identifying potential treatment targets. However, only the primate eye resembles the human eye to a degree where most structures are nearly identical. Some research questions can therefore only be answered using a nonhuman primate (NHP) model. In this review, we want to summarize these key features and highlight the importance of the NHP model for gene therapy development in ophthalmology.


Phages and their satellites encode hotspots of antiviral systems.
Bacteria carry diverse genetic systems to defend against viral infection, some of which are found within prophages where they inhibit competing viruses. Phage satellites pose additional pressures on phages by hijacking key viral elements to their own benefit. Here, we show that E. coli P2-like phages and their parasitic P4-like satellites carry hotspots of genetic variation containing reservoirs of anti-phage systems. We validate the activity of diverse systems and describe PARIS, an abortive infection system triggered by a phage-encoded anti-restriction protein. Antiviral hotspots participate in inter-viral competition and shape dynamics between the bacterial host, P2-like phages, and P4-like satellites. Notably, the anti-phage activity of satellites can benefit the helper phage during competition with virulent phages, turning a parasitic relationship into a mutualistic one. Anti-phage hotspots are present across distant species and constitute a substantial source of systems that participate in the competition between mobile genetic elements.


A systematic review, and meta-analysis, examining the prevalence of price promotions on foods and whether they are more likely to be found on less-healthy foods.
There are concerns that price promotions encourage unhealthy dietary choices. This review aims to answer the following research questions (RQ1) what is the prevalence of price promotions on foods in high-income settings, and (RQ2) are price promotions more likely to be found on unhealthy foods? Systematic review of articles published in English, in peer-review journals, after 1 January 2000. Included studies measured the prevalence of price promotions (i.e. percentage of foods carrying a price promotion out of the total number of foods available to purchase) in retail settings, in upper-mid to high-income countries. 'Price promotion' was defined as a consumer-facing temporary price reduction or discount available to all customers. The control group/comparator was the equivalent products without promotions. The primary outcome for this review was the prevalence of price promotions, and the secondary outcome was the difference between the proportions of price promotions on healthy and unhealthy foods. Nine studies (239 344 observations) were included for the meta-analysis for RQ1, the prevalence of price promotions ranged from 6 % (95 % CI 2 %, 15 %) for energy-dense nutrient-poor foods to 15 % (95 % CI 9 %, 25 %) for cereals, grains, breads and other starchy carbohydrates. However, the I-squared statistic was 99 % suggesting a very high level of heterogeneity. Four studies were included for the analysis of RQ2, of which two supported the hypothesis that price promotions were more likely to be found on unhealthy foods. The prevalence of price promotions is very context specific, and any proposed regulations should be supported by studies conducted within the proposed setting(s).


The association between reading abilities and visual-spatial attention in Hong Kong Chinese children.
A growing body of research suggests that visual-spatial attention is important for reading achievement. However, few studies have been conducted in non-alphabetic orthographies. This study extended the current research to reading development in Chinese, a logographic writing system known for its visual complexity. Eighty Hong Kong Chinese children were selected and divided into poor reader and typical reader groups, based on their performance on the measures of reading fluency, Chinese character reading, and reading comprehension. The poor and typical readers were matched on age and nonverbal intelligence. A Posner's spatial cueing task was adopted to measure the exogenous and endogenous orienting of visual-spatial attention. Although the typical readers showed the cueing effect in the central cue condition (i.e., responses to targets following valid cues were faster than those to targets following invalid cues), the poor readers did not respond differently in valid and invalid conditions, suggesting an impairment of the endogenous orienting of attention. The two groups, however, showed a similar cueing effect in the peripheral cue condition, indicating intact exogenous orienting in the poor readers. These findings generally supported a link between the orienting of covert attention and Chinese reading, providing evidence for the attentional-deficit theory of dyslexia.


Tubby-like protein 1 (TULP1) interacts with F-actin in photoreceptor cells.
TULP1 is a photoreceptor-specific protein of unknown function that, when mutated, can cause retinitis pigmentosa in humans and photoreceptor degeneration in mice. Toward a better understanding of the role of TULP1 in retinal disease, its subcellular localization was sought and the TULP1 protein binding partners identified. Immunocytochemistry and subcellular fractionation were used to determine the localization of TULP1 and actin in COS7 cells and photoreceptor cells. Immunoprecipitation from retinal lysates followed by liquid chromatography tandem mass spectrometry and in vitro binding assays was used to identify TULP1-binding partners. Phospholipid binding assays were performed with a commercially available kit. TULP1 localizes at or near the plasma membrane and associates with the membranous fraction of COS7 cells, probably through binding phosphorylated phospholipids. In addition, TULP1 partitions to the aqueous phase during Triton X-114 extraction. Immunoprecipitation from retinal lysate identified F-actin as a possible TULP1-binding partner. Co-sedimentation assays further support an interaction between TULP1 and actin. In photoreceptor cells, actin and TULP1 colocalize at the inner segment, connecting cilium, and outer limiting membrane. TULP1 is a cytoplasmic protein that associates with cellular membranes and the cytoskeleton. TULP1 and actin appear to interact and colocalize in photoreceptor cells of the retina. TULP1 may be involved in actin cytoskeletal functions such as protein trafficking that takes place at or near the plasma membrane from the inner segment through the connecting cilium into the outer segment of photoreceptor cells.


Pedometer-based Exercise Interventions for Patients with Breast Cancer Receiving Chemotherapy - A Systematic Review.
Exercises such as walking are prescribed for the patients with breast cancer receiving chemotherapy, but only a few studies include pedometers in conjunction with the routine exercises prescribed. Thus, the aim was to find if the adherence and performance of exercise is improved or has no impact if coupled with the physical activity monitors. A systematic search using the keywords was conducted in PubMed Central, CINAHL, Embase, Cochrane Library, and Scopus. The search revealed 275 articles, of which 3 randomized controlled trials were selected for qualitative analysis based on the inclusion and exclusion criteria for the review. The three studies retrieved by the systematic review have used different protocols of pedometer-based walking on patients with breast cancer undergoing chemotherapy and studied the following outcome measures: fatigue, body composition, quality of life, and psychological factors. The evidence obtained from the review suggests that pedometer-based walking programs have a positive impact on cancer-related fatigue and overall quality of life of patients with breast cancer receiving chemotherapy.


Integrative Review of the Literature on Hispanics and Hospice.
The provision of optimal end-of-life care to Hispanics receiving hospice care requires familiarity with hospice-specific variables. For example, a preference for nondisclosure of terminal prognosis in some Hispanics is incongruous with traditional hospice practice. In addition, the Spanish word for hospice, "hospicio," has negative connotations about abandonment of loved ones. Added to cultural considerations are socioeconomic considerations. Many marginalized Hispanic individuals may experience distinct challenges when enrolling in hospice due to socioeconomic hardships relating to poverty, citizenship, and lack of insurance. This systematic integrative review examines the research literature on Hispanics and hospice to report on the state of the science for this topic. Reviewed articles were identified systematically using computer research databases and inclusion and exclusion criteria. Of the 21 reviewed articles, many are survey and low-inference qualitative designs with limited validity and trustworthiness. Most survey instruments were not validated for Spanish language or Hispanic culture. None of the qualitative studies included theoretical sampling or follow-up interviews. Few study designs considered heterogeneity within the Hispanic population. Interpreting results cautiously, there is evidence that some Hispanics find some satisfaction with hospice care in spite of cultural incongruities and socioeconomic challenges. Future research calls for intervention studies and high-inference qualitative designs to gain insight into hospice experiences and what constitutes quality hospice care from the perspectives of Hispanic subgroups. Assessing quality and designing interventions for these end-of-life cultural and socioeconomic issues will improve end-of-life care and facilitate the hospice philosophy of promoting emotional growth at end of life.


Protective practices against zoonotic infections among rural and slum communities from South Central Chile.
Despite well-recognized recommendations to reduce human exposure to zoonotic pathogens, the use of personal and herd-level protective practices is inconsistent in communities where human interactions with animals are common. This study assessed household-level participation in rodent- (extermination, proper food storage, trash disposal), occupational- (preventive veterinary care, boot-wearing, glove-wearing), and garden-associated (restricting animal access, boot-wearing, glove-wearing) protective practices in farms, villages, and slums in the Los Rios region, Chile, where zoonotic pathogens are endemic. Questionnaires administered at 422 households across 12 communities recorded household-level socio-demographic characteristics and participation in nine protective practices. Household inclusion in the analysis of occupational practices required having livestock and a household member with occupational exposure to livestock (n = 127), and inclusion in analysis of garden practices required having a garden and at least one animal (n = 233). The proportion of households participating in each protective practice was compared across community types through chi-square analyses. Mixed effects logistic regression assessed household-level associations between socio-demographic characteristics and participation in each protective practice. Most households (95.3 %) reported participation in rodent control, and a positive association between the number of rodent signs in a household and rodent extermination was observed (OR: 1.75, 95 % CI: 1.41, 2.16). Occupational protective practices were reported in 61.8 % of eligible households; household size (OR: 1.63, 95 % CI: 1.17, 5.84) and having children (OR: 0.22, 95 % CI: 0.06, 0.78) were associated with preventive veterinary care. Among eligible households, 73.8 % engaged in protective practices when gardening, and species diversity was positively associated with wearing boots (OR: 1.27, 95 % CI: 1.03, 1.56). Household-level participation in all three protective practices within any exposure category was limited (<10.4 %) and participation in any individual protective practice varied considerably within and across community types. The levels of participation in protective practices reported in this study are consistent with descriptions in the literature of imperfect use of methods that reduce human exposure to zoonotic pathogens. The wide differences across communities in the proportion of households participating in protective practices against human exposure to zoonotic pathogens, suggests that future research should identify community-level characteristics that influence household participation in such practices.


Data analysis in oral history: A new approach in historical research.
Historical research has limitations in applying proper and credit-worthy chronology to clarify the data. In this methodology, the application of oral history is one of the ways in which answers to questions addressed by the research theme are elicited. Oral history, as a clear and transparent tool, needs to be applied with guidelines for qualitative researchers regarding data analysis limitations from oral evidence and face-to-face contact. Therefore, the development of a systematic method for data analysis is needed to obtain accurate answers, based on which a credit-worthy narration can be produced. The aim of this study was to introduce an ethical and objective approach for the analysis of data obtained from oral history. This is a methodological article that suggests an analysis method based on qualitative approach and experiences of the authors. A systematic method of data analysis for oral history research, based on common qualitative data analysis methods, has been suggested as the result of this article. This new technique is equipped with measures that would assist qualitative researchers in the nursing field and other disciplines regarding analysis of qualitative data resulting from oral history studies.


Phospholipase C-gamma1 is required for cell survival in oxidative stress by protein kinase C.
Phospholipase C-gamma1 (PLC-gamma1) activation has been reported to enhance cell survival during the cellular response to oxidative stress. We studied the role of protein kinase C (PKC) pathways in mediating PLC-gamma1 survival signalling in oxidative stress by using mouse embryonic fibroblasts genetically deficient in PLC-gamma1 (Plcg1(-/-)) and its wild type (Plcg1(+/+)). PLC-gamma1 was activated by H(2)O(2) treatment in a dose- and time-dependent manner. Activation of PKC was also markedly increased in both cell lines treated with H(2)O(2) (1-5 mM), but with low doses (50-200 microM), PKC activation was considerably decreased in Plcg1(-/-) cells. After treatment with H(2)O(2), PKC-dependent phosphorylation of Bcl-2 and cell viability of Plcg1(-/-) cells decreased dramatically and caspase-3-like activity increased significantly compared with that of the wild-type cells. Furthermore, pretreatment of Plcg1(+/+) cells with PKC-specific inhibitor decreased levels of PKC-dependent Bcl-2 phosphorylation, enhanced caspase-3 activity and their sensitivity to H(2)O(2). On the contrary, treatment of Plcg1(-/-) cells with PKC-specific activator increased the Bcl-2 phosphorylation, decreased caspase-3 activity and improved their survival. These results suggest that PLC-gamma1 mediates survival signalling in oxidative-stress response by PKC-dependent phosphorylation of Bcl-2 and inhibition of caspase-3.


Δ9-Tetrahydrocannabinolic Acid markedly alleviates liver fibrosis and inflammation in mice.
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, and it is closely associated to obesity, type 2 diabetes mellitus, and dyslipidemia. Medicinal cannabis and some neutral cannabinoids have been suggested as a potential therapy for liver diseases. Δ9-tetrahydrocannabinolic acid (Δ9-THCA), the non-psychotropic precursor of Δ9-THC, is one of the most abundant cannabinoids presents in Cannabis Sativa. However, its biological activities have been poorly investigated. Herein, we studied the antifibrotic and antiinflammatory activities of Δ9-THCA in two different animal models of liver injury, providing a rationale for additional studies on the medicinal use of this cannabinoid in the treatment of liver fibrosis and the management of NAFLD. The antifibrotic activity of Δ9-THCA in vitro was investigated in the cell lines LX-2 and NIH-3T3-Col1A2-luc. Non-alcoholic liver fibrosis was induced in mice by CCl4 treatment or, alternatively, by 23-week high fat diet (HFD) feeding. Δ9-THCA was administered daily intraperitoneally during the CCl4 treatment or during the last 3 weeks in HFD-fed mice. TGFβ-induced profibrotic gene expression was analyzed by luciferase and qPCR assays. Liver fibrosis and inflammation were assessed by immunochemistry and qPCR. Blood glucose, insulin, leptin and triglyceride levels were measured in HFD mice. Δ9-THCA inhibited the expression of Tenascin C (TNC) and Col3A1 induced by TGFβ in LX-2 cells and the transcriptional activity of the Col1A2 promoter in fibroblasts. Δ9-THCA significantly attenuated CCl4-induced liver fibrosis and inflammation and reduced T cell and macrophage infiltration. Mice fed HFD for 23 weeks developed severe obesity (DIO), fatty liver and marked liver fibrosis, accompanied by immune cell infiltration. Δ9-THCA, significantly reduced body weight and adiposity, improved glucose tolerance, and drastically attenuated DIO-induced liver fibrosis and immune cell infiltration. Δ9-THCA prevents TGFβ-induced fibrotic markers in vitro and liver inflammation and fibrogenesis in vivo, providing a rationale for additional studies on the medicinal use of this cannabinoid, as well as cannabis preparations containing it, for the treatment of liver fibrosis and the management of NAFLD.


Intergroup Contact and Social Change: Implications of Negative and Positive Contact for Collective Action in Advantaged and Disadvantaged Groups.
Previous research has shown that (a) positive intergroup contact with an advantaged group can discourage collective action among disadvantaged-group members and (b) positive intergroup contact can encourage advantaged-group members to take action on behalf of disadvantaged outgroups. Two studies investigated the effects of negative as well as positive intergroup contact. Study 1 ( n = 482) found that negative but not positive contact with heterosexual people was associated with sexual-minority students' engagement in collective action (via group identification and perceived discrimination). Among heterosexual students, positive and negative contacts were associated with, respectively, more and less LGB (lesbian, gay, bisexual) activism. Study 2 ( N = 1,469) found that only negative contact (via perceived discrimination) predicted LGBT (lesbian, gay, bisexual, and transgender) students' collective action intentions longitudinally while only positive contact predicted heterosexual/cisgender students' LGBT activism. Implications for the relationship between intergroup contact, collective action, and social change are discussed.


Development of an Immunosensor Based on Layered Double Hydroxides for MMR Cancer Biomarker Detection.
As a potential biomarker for the investigation of cancer inflammatory profiles, macrophage mannose receptor (MMR, CD206) is herein selected to develop an immunosensor based on layered double hydroxide (LDH). Like an endocyte C-type lectin receptor, MMR plays an important role in immune homeostasis by scavenging unwanted mannose glycoproteins. It attracts a progressive attention thanks to its particularly high expression within the tumor microenvironment. There is a great of interest to develop an immunosensor based on an antibody specific to MMR for detection of stroma versus tumor cells. In this work, we studied the feasibility of high sensitive MMR cancer Screen Printed Electrode (SPE) immunosensor. Working electrode of commercialized SPE was modified by immobilization of specific antibody (anti-MMR) into thin layer of LDH nanomaterials. Structural, morphological, and surface properties of LDHs were studied by X-Ray diffraction, atomic force microscopy and Infrared spectroscopy in ATR. Cyclic Voltammetry technique was used to study interaction between the human recombinant MMR protein (rHu-MMR, NSO derived) and an immobilized antibody into developed immunosensor. High specific response of -11.72 μA/ng.mL(-1) (with a correlation coefficient of R(2)=0.994 ) were obtained in linear range of 0.05 ng/mL to 10.0 ng/mL of specific recombinant antigen. The limit of detection (LOD) was less than 15.0 pg/mL. From these attractive results, the feasibility of an electrochemical immunosensor for cancer was proved. Additional experiments to study stability and reproducibility the immunosensor should be completed in perspective to use these anti-MMR based immunosensors for sensing human MMR in patient biopsies and sera.


Genetic neuroscience of mammalian learning and memory.
Our primary research interest is to understand the molecular and cellular mechanisms on neuronal circuitry underlying the acquisition, consolidation and retrieval of hippocampus-dependent memory in rodents. We study these problems by producing genetically engineered (i.e. spatially targeted and/or temporally restricted) mice and analysing these mice by multifaceted methods including molecular and cellular biology, in vitro and in vivo physiology and behavioural studies. We attempt to identify deficits at each of the multiple levels of complexity in specific brain areas or cell types and deduce those deficits that underlie specific learning or memory. We will review our recent studies on the acquisition, consolidation and recall of memories that have been conducted with mouse strains in which genetic manipulations were targeted to specific types of cells in the hippocampus or forebrain of young adult mice.


Kidney effects in long term exposed lead smelter workers.
Occupational exposure to lead may cause kidney damage. This study was carried out on a cohort of 70 active and 30 retired long term exposed lead smelter workers. Their kidney function was compared with 31 active and 10 retired truck assembly workers who had no occupational exposure to lead. The lead workers had been regularly followed up with measurements of lead concentration in blood since 1950. Previous exposure to lead was calculated as a time integrated blood lead index for each worker. Blood and urine samples were obtained from all subjects. The concentration of lead in blood (B-Pb) and urine (U-Pb) was analysed. The urinary concentrations of several sensitive indicators of early tubular (U-beta 2-microglobulin (U-beta 2-m); U-N-acetyl-beta-glucosaminidase (U-NAG)) and glomerular kidney damage (U-albumin) were determined. The B-Pb and U-Pb values were significantly higher among active and retired lead workers compared with their corresponding control groups. The highest concentrations were found among the active lead workers. The concentrations of the parameters of kidney function investigated were of the same magnitude for exposed workers and controls. No clinical signs of renal impairment were found among the workers. No correlations of clinical importance existed between concentrations of U-albumin, U-beta 2-m, and U-NAG activity on the one hand and the concentrations of B-Pb, cumulative blood lead index, U-Pb, and lead concentrations in the calcaneus and tibia on the other, among lead workers and controls. Despite many years of moderate to heavy exposure to lead, particularly for the retired lead workers, no signs of adverse effects on the kidney such as early tubular or glomerular malfunction were found. Reversible changes in kidney function during the 1950s and 1960s could not be excluded, however, due to a greater exposure to lead during that time.


Impacts of tropical cyclones on U.S. forest tree mortality and carbon flux from 1851 to 2000.
Tropical cyclones cause extensive tree mortality and damage to forested ecosystems. A number of patterns in tropical cyclone frequency and intensity have been identified. There exist, however, few studies on the dynamic impacts of historical tropical cyclones at a continental scale. Here, we synthesized field measurements, satellite image analyses, and empirical models to evaluate forest and carbon cycle impacts for historical tropical cyclones from 1851 to 2000 over the continental U.S. Results demonstrated an average of 97 million trees affected each year over the entire United States, with a 53-Tg annual biomass loss, and an average carbon release of 25 Tg y(-1). Over the period 1980-1990, released CO(2) potentially offset the carbon sink in forest trees by 9-18% over the entire United States. U.S. forests also experienced twice the impact before 1900 than after 1900 because of more active tropical cyclones and a larger extent of forested areas. Forest impacts were primarily located in Gulf Coast areas, particularly southern Texas and Louisiana and south Florida, while significant impacts also occurred in eastern North Carolina. Results serve as an important baseline for evaluating how potential future changes in hurricane frequency and intensity will impact forest tree mortality and carbon balance.


Temporal dynamics in an immunological synapse: Role of thermal fluctuations in signaling.
The article analyzes the contribution of stochastic thermal fluctuations in the attachment times of the immature T-cell receptor TCR: peptide-major-histocompatibility-complex pMHC immunological synapse bond. The key question addressed here is the following: how does a synapse bond remain stabilized in the presence of high-frequency thermal noise that potentially equates to a strong detaching force? Focusing on the average time persistence of an immature synapse, we show that the high-frequency nodes accompanying large fluctuations are counterbalanced by low-frequency nodes that evolve over longer time periods, eventually leading to signaling of the immunological synapse bond primarily decided by nodes of the latter type. Our analysis shows that such a counterintuitive behavior could be easily explained from the fact that the survival probability distribution is governed by two distinct phases, corresponding to two separate time exponents, for the two different time regimes. The relatively shorter timescales correspond to the cohesion:adhesion induced immature bond formation whereas the larger time reciprocates the association:dissociation regime leading to TCR:pMHC signaling. From an estimate of the bond survival probability, we show that, at shorter timescales, this probability P(Δ)(τ) scales with time τ as a universal function of a rescaled noise amplitude D/Δ(2), such that P(Δ)(τ)∼τ(-(Δ/√[D]+1/2)),Δ being the distance from the mean intermembrane (T cell:Antigen Presenting Cell) separation distance. The crossover from this shorter to a longer time regime leads to a universality in the dynamics, at which point the survival probability shows a different power-law scaling compared to the one at shorter timescales. In biological terms, such a crossover indicates that the TCR:pMHC bond has a survival probability with a slower decay rate than the longer LFA-1:ICAM-1 bond justifying its stability.


Cardiovascular morbidity and mortality associated with the metabolic syndrome.
To estimate the prevalence of and the cardiovascular risk associated with the metabolic syndrome using the new definition proposed by the World Health Organization A total of 4,483 subjects aged 35-70 years participating in a large family study of type 2 diabetes in Finland and Sweden (the Botnia study) were included in the analysis of cardiovascular risk associated with the metabolic syndrome. In subjects who had type 2 diabetes (n = 1,697), impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) (n = 798) or insulin-resistance with normal glucose tolerance (NGT) (n = 1,988), the metabolic syndrome was defined as presence of at least two of the following risk factors: obesity, hypertension, dyslipidemia, or microalbuminuria. Cardiovascular mortality was assessed in 3,606 subjects with a median follow-up of 6.9 years. In women and men, respectively, the metabolic syndrome was seen in 10 and 15% of subjects with NGT, 42 and 64% of those with IFG/IGT, and 78 and 84% of those with type 2 diabetes. The risk for coronary heart disease and stroke was increased threefold in subjects with the syndrome (P < 0.001). Cardiovascular mortality was markedly increased in subjects with the metabolic syndrome (12.0 vs. 2.2%, P < 0.001). Of the individual components of the metabolic syndrome, microalbuminuria conferred the strongest risk of cardiovascular death (RR 2.80; P = 0.002). The WHO definition of the metabolic syndrome identifies subjects with increased cardiovascular morbidity and mortality and offers a tool for comparison of results from diferent studies.


Effects of Neoadjuvant Chemotherapy on Benign Breast Lesions Compared to Cancers: Should an Additional Lesion on Magnetic Resonance Imaging Responding Similar to Cancer after Neoadjuvant Chemotherapy be Viewed with Suspicion?
Determining the effects of neoadjuvant chemotherapy (NAC) on benign breast lesions and to evaluate their response in comparison to breast cancers. A retrospective analysis performed on breast cancer patients between 2008 and 2014 to identify patients who had a pre- and post-NAC magnetic resonance imaging (MRI) and biopsy-proven benign lesions. Pre- and post-NAC size and intensity of enhancement of benign lesions and cancers were measured. Breast glandularity and background enhancement were graded. A 2 × 2 repeated measures ANOVAs and Sidak post hoc tests were conducted for multiple comparisons. Paired t-tests were conducted to examine changes over time, and two-tailed P values were reported. The effects of NAC in 38 cancers were compared to the effects of NAC in 47 benign lesions in these patients. From pre- to post-NAC, the mean size (cm) of malignant lesions on MRI decreased from 4.09 (±standard deviation [SD] 2.51) to 1.54 (±SD 2.32), (P < 0.001); the mean size (cm) of benign lesions decreased from 0.83 (±SD 0.54 cm) to 0.28 (±SD 0.51), (P < 0.001). Both benign and malignant lesions decreased in size after NAC, the size reduction in malignant lesions was significantly greater than benign lesions. From pre- to post-NAC, the mean lesion enhancement of the malignant lesions (scale 1-4) decreased from 3.43 (±SD 0.80) to 1.02 (±SD 1.34); the mean lesion enhancement of benign lesions decreased from 2.96 (±SD 1.04) to 0.98 (±SD 1.51). For both benign and malignant lesions, there was a significant overall reduction in enhancement after NAC from moderate at pre-NAC to minimal at post-NAC, P < 0.001. There was no overall difference in the enhancement of cancers (mean = 2.22, SD = 0.79) versus benign lesions (mean = 1.97, SD = 1.08), (P = 0.23). There was no significant change in glandularity from pretherapy (mean = 3.11, SD = 0.84) to posttherapy (mean = 3.13, SD = 0.82), P < 0.001. Similar to cancers, benign breast lesions also show a significant decrease in size and enhancement after NAC; however, the decrease in size is less compared to cancers.


Effect of coexisting vascular disease on long-term risk of recurrent events after TIA or stroke.
To determine whether patients with TIA or ischemic stroke with coexisting cardiovascular disease (i.e., history of coronary or peripheral artery disease) are still at high risk of recurrent ischemic events despite current secondary prevention guidelines. In a population-based study in Oxfordshire, UK (Oxford Vascular Study), we studied consecutive patients with TIA or ischemic stroke for 2002-2014. Patients were treated according to current secondary prevention guidelines and we determined risks of coronary events, recurrent ischemic stroke, and major bleeding stratified by the presence of coexisting cardiovascular disease. Among 2,555 patients (9,148 patient-years of follow-up), those (n = 640; 25.0%) with coexisting cardiovascular disease (449 coronary only; 103 peripheral only; 88 both) were at higher 10-year risk of coronary events than those without (22.8%, 95% confidence interval 17.4-27.9; vs 7.1%, 5.3-8.8; p < 0.001; age- and sex-adjusted hazard ratio [HR] 3.07, 2.24-4.21) and of recurrent ischemic stroke (31.5%, 25.1-37.4; vs 23.4%, 20.5-26.2; p = 0.0049; age- and sex-adjusted HR 1.23, 0.99-1.53), despite similar rates of use of antithrombotic and lipid-lowering medication. However, in patients with noncardioembolic TIA/stroke, risk of extracranial bleeds was also higher in those with coexisting cardiovascular disease, particularly in patients aged <75 years (8.1%, 2.8-13.0; vs 3.4%, 1.6-5.3; p = 0.0050; age- and sex-adjusted HR 2.71, 1.16-6.30), although risk of intracerebral hemorrhage was not increased (age- and sex-adjusted HR 0.36, 0.04-2.99). As in older studies, patients with TIA/stroke with coexisting cardiovascular disease remain at high risk of recurrent ischemic events despite current management. More intensive lipid-lowering might therefore be justified, but benefit from increased antithrombotic treatment might be offset by the higher risk of extracranial bleeding.


HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response.
The mechanism by which the MHC class I allele, HLA-B27, contributes to spondyloarthritis pathogenesis is unknown. In contrast to other alleles that have been examined, HLA-B27 has a tendency to form high m.w. disulfide-linked H chain complexes in the endoplasmic reticulum (ER), bind the ER chaperone BiP/Grp78, and undergo ER-associated degradation. These aberrant characteristics have provided biochemical evidence that HLA-B27 is prone to misfold. Recently, similar biochemical characteristics of HLA-B27 were reported in cells from HLA-B27/human beta2-microglobulin transgenic (HLA-B27 transgenic) rats, an animal model of spondyloarthritis, and correlated with disease susceptibility. In this study, we demonstrate that the unfolded protein response (UPR) is activated in macrophages derived from the bone marrow of HLA-B27 transgenic rats with inflammatory disease. Microarray analysis of these cells also reveals an IFN response signature. In contrast, macrophages derived from premorbid rats do not exhibit a strong UPR or evidence of IFN exposure. Activation of macrophages from premorbid HLA-B27 transgenic rats with IFN-gamma increases HLA-B27 expression and leads to UPR induction, while no UPR is seen in cells from nondisease-prone HLA-B7 transgenic or wild-type (nontransgenic) animals. This is the first demonstration, to our knowledge, that HLA-B27 misfolding is associated with ER stress that results in activation of the UPR. These observations link HLA-B27 expression with biological effects that are independent of immunological recognition, but nevertheless may play an important role in the pathogenesis of inflammatory diseases associated with this MHC class I allele.


Acupuncture anesthesia and analgesia for clinical acute pain in Japan.
Acupuncture anesthesia has been practiced in China since about 1960. In Japan, Hyodo reported 30 cases of acupuncture anesthesia in 1972. However, from around 1980, the direction of acupuncture investigations turned from anesthesia to analgesia. Acupuncture analgesia is presently considered a way to activate the body's endogenous analgesic system. Recently, with the rise of acupuncture as one of the most well known CAM therapies, acupuncture or moxibustion treatment has been reported for both acute and chronic pain. Even so, few clinical reports and original articles have been reported in Japan. This review illustrates how acupuncture is being used in Japan for acute pain such as surgical operations, post- operative pain (POP), neuropathic pain, pain associated with teeth extractions and after the extraction of impacted wisdom teeth.


Aberrant expression of E-cadherin and beta-catenin in human prostate cancer.
Cadherin-catenin complexes play a key role in embryonic development, and are associated with carcinogenesis and metastasis. We studied the expression of the major members of the family, including E-cadherin and beta-catenin in prostate cancer (PC), and correlated with Gleason grade and pathologic stage. Immunohistochemistry was performed on serial sections of paraffinized radical prostatectomy specimens to evaluate E-cadherin (n = 16) and beta-catenin (n = 17) expression using heat induced epitope retrieval. Benign appearing prostate epithelium was used as an internal control in each specimen. Two pathologists independently reviewed and scored the intensity and extent of immunostaining using a semiquantitative scale. The Mantel-Haenszel method, stratified by reviewer, was used to test for an association among Gleason score, pathologic stage, and the expression of E-cadherin or beta-catenin in PC. Gleason grade > or =7 cancers showed significantly lower expression of E-cadherin and beta-catenin compared to Gleason grade < 7 PC, P = 0.015 and 0.025, respectively. In addition, beta-catenin was down regulated in 4 of 5 (80%) specimens with identifiable high-grade prostatic intraepithelial neoplasia and had demonstrable nuclear staining in higher grade PC (P = 0.0001). However, E-cadherin and beta-catenin membranous or nuclear expressions were not significantly associated with final pathologic stage of the specimens (P values >0.05). Overall, the expression of E-cadherin and beta-catenin is significantly down regulated in PC compared to surrounding benign appearing prostate, which correlates with increasing Gleason grade. Furthermore, nuclear localization of beta-catenin in high grade PC may be a useful biomarker for aggressive PC.


New bandwidth selection criterion for Kernel PCA: approach to dimensionality reduction and classification problems.
DNA microarrays are potentially powerful technology for improving diagnostic classification, treatment selection, and prognostic assessment. The use of this technology to predict cancer outcome has a history of almost a decade. Disease class predictors can be designed for known disease cases and provide diagnostic confirmation or clarify abnormal cases. The main input to this class predictors are high dimensional data with many variables and few observations. Dimensionality reduction of these features set significantly speeds up the prediction task. Feature selection and feature transformation methods are well known preprocessing steps in the field of bioinformatics. Several prediction tools are available based on these techniques. Studies show that a well tuned Kernel PCA (KPCA) is an efficient preprocessing step for dimensionality reduction, but the available bandwidth selection method for KPCA was computationally expensive. In this paper, we propose a new data-driven bandwidth selection criterion for KPCA, which is related to least squares cross-validation for kernel density estimation. We propose a new prediction model with a well tuned KPCA and Least Squares Support Vector Machine (LS-SVM). We estimate the accuracy of the newly proposed model based on 9 case studies. Then, we compare its performances (in terms of test set Area Under the ROC Curve (AUC) and computational time) with other well known techniques such as whole data set + LS-SVM, PCA + LS-SVM, t-test + LS-SVM, Prediction Analysis of Microarrays (PAM) and Least Absolute Shrinkage and Selection Operator (Lasso). Finally, we assess the performance of the proposed strategy with an existing KPCA parameter tuning algorithm by means of two additional case studies. We propose, evaluate, and compare several mathematical/statistical techniques, which apply feature transformation/selection for subsequent classification, and consider its application in medical diagnostics. Both feature selection and feature transformation perform well on classification tasks. Due to the dynamic selection property of feature selection, it is hard to define significant features for the classifier, which predicts classes of future samples. Moreover, the proposed strategy enjoys a distinctive advantage with its relatively lesser time complexity.


Clinical and Patient-reported Outcomes in Patients with Psoriatic Arthritis (PsA) by Body Surface Area Affected by Psoriasis: Results from the Corrona PsA/Spondyloarthritis Registry.
Psoriatic arthritis (PsA) is commonly comorbid with psoriasis; the extent of skin lesions is a major contributor to psoriatic disease severity/burden. We evaluated whether extent of skin involvement with psoriasis [body surface area (BSA) > 3% vs ≤ 3%] affects overall clinical and patient-reported outcomes (PRO) in patients with PsA. Using the Corrona PsA/Spondyloarthritis Registry, patient characteristics, disease activity, and PRO at registry enrollment were assessed for patients with PsA aged ≥ 18 years with BSA > 3% versus ≤ 3%. Regression models were used to evaluate associations of BSA level with outcome [modified minimal disease activity (MDA), Health Assessment Questionnaire (HAQ) score, patient-reported pain and fatigue, and the Work Productivity and Activity Impairment questionnaire score]. Adjustments were made for age, sex, race, body mass index, disease duration, and history of biologics, disease-modifying antirheumatic drug, and prednisone use. This analysis included 1240 patients with PsA with known BSA level (n = 451, BSA > 3%; n = 789, BSA ≤ 3%). After adjusting for potential confounding variables, patients with BSA > 3% versus ≤ 3% had greater patient-reported pain and fatigue and higher HAQ scores (p = 2.33 × 10-8, p = 0.002, and p = 1.21 × 10-7, respectively), were 1.7× more likely not to be in modified MDA (95% CI 1.21-2.41, p = 0.002), and were 2.1× more likely to have overall work impairment (1.37-3.21, p = 0.0001). These Corrona Registry data show that substantial skin involvement (BSA > 3%) is associated with greater PsA disease burden, underscoring the importance of assessing and effectively managing psoriasis in patients with PsA because this may be a contributing factor in PsA severity.


The Effectiveness of Community Health Workers for CVD Prevention in LMIC.
Community health workers (CHW) may be effective in tackling the burden of cardiovascular diseases in low- and middle-income countries (LMIC). This review examines whether CHWs can improve the identification and control of cardiovascular risk factors in LMIC. We searched for studies that used CHW as a basis for cardiovascular risk factor management. Our search yielded 11 articles that targeted cardiovascular risk factor assessment, hypertension, diabetes, smoking, diet and physical activity. There were 4 randomized controlled trials, 3 quasi-experimental studies, 3 cross-sectional studies, and 1 retrospective analysis. Eight studies reported positive results with CHW being able to effectively screen for cardiovascular risk factors, decrease systolic blood pressure, decrease fasting blood glucose, increase quit rates of smoking, decrease weight, and improve diet and physical activity. Our review demonstrates that CHW may be effective in helping tackle the burden of cardiovascular disease in LMIC.


Imaging tumor burden in the brain with 89Zr-transferrin.
A noninvasive technology that indiscriminately detects tumor tissue in the brain could substantially enhance the management of primary or metastatic brain tumors. Although the documented molecular heterogeneity of diseases that initiate or eventually deposit in the brain may preclude identifying a single smoking-gun molecular biomarker, many classes of brain tumors are generally avid for transferrin. Therefore, we reasoned that applying a radiolabeled derivative of transferrin ((89)Zr-labeled transferrin) may be an effective strategy to more thoroughly identify tumor tissue in the brain, regardless of the tumor's genetic background. Transferrin was radiolabeled with (89)Zr, and its properties with respect to human models of glioblastoma multiforme were studied in vivo. In this report, we show proof of concept that (89)Zr-labeled transferrin ((89)Zr-transferrin) localizes to genetically diverse models of glioblastoma multiforme in vivo. Moreover, we demonstrate that (89)Zr-transferrin can detect an orthotopic lesion with exceptional contrast. Finally, the tumor-to-brain contrast conferred by (89)Zr-transferrin vastly exceeded that observed with (18)F-FDG, currently the most widely used radiotracer to assess tumor burden in the brain. The results from this study suggest that (89)Zr-transferrin could be a broadly applicable tool for identifying and monitoring tumors in the brain, with realistic potential for near-term clinical translation.


Rates of seasonal affective disorder in children and adolescents.
The authors estimated the frequency of seasonal affective disorder in children and adolescents and examined the relationship of this rate to age and pubertal status. A modified version of the Seasonal Pattern Assessment Questionnaire was distributed to 2,267 students at a middle school and a high school in a suburb of Washington, D.C. A case diagnosis was made if the respondent scored over 18 and also indicated that the change of seasons was at least a "pretty bad" problem. A total of 1,871 questionnaires (82.5%) were returned. Sixty probable cases of seasonal affective disorder (3.3%) were identified among the 1,835 surveys analyzed. Age was directly correlated with the frequency of seasonal affective disorder, and the rate was higher in postpubertal girls. Differences between the subjects with and without identified cases of seasonal affective disorder were seen in the symptom endorsement patterns, particularly for "feel worst," "least energy," "most irritable," and "socialize least." These pilot data suggest that between 1.7% and 5.5% of 9-19-year-old children may have seasonal affective disorder. Further research is warranted, particularly that which examines the relationship between seasonal affective disorder and puberty.


PET imaging of glioblastoma multiforme EGFR expression for therapeutic decision guidance.
After initial therapy and total resection of glioblastoma multiforme (GBM), 80-90% of recurrences occur at the surgical margins. Insufficient sensitivity and specificity of current imaging techniques based on non-specific vascular imaging agents lead to delay in diagnosis of residual and/or recurrent disease. A tumor-specific imaging agent for GBM may improve detection of small residual disease in the post-operative period, and improve ability to distinguish tumor recurrence from its imaging mimics that can delay diagnosis. To this end, we developed an EGFR-targeted PET probe and assessed its ability to image EGFR WT (U87) and EGFRvIII (Gli36vIII) expressing GBMs in both murine intra-cranial xenografts and in a surgical-resection model. The developed imaging probe, (64)Cu-DOTAcetuximab-F(ab´)2, binds with a Kd of 11.2 nM to EGFR expressing GBM. (64)Cu-DOTA-cetuximab-F(ab´)2 specifically localized to intra-cranial tumor with a significant difference in SUVmean between tumor and contralateral brain for both Gli36vIII and U87 tumors (P<0.01 for both comparisons), with mean TBR of 22.5±0.7 for Gli36vIII tumors and 28.9±2.1 for U87 tumors (TBR±SEM). Tracer uptake by tumor was significantly inhibited by pre-injection with cetuximab (P<0.01 for both), with SUVmean reduced by 68% and 58% for Gli36vIII and U87 tumors, respectively. Surgical resection model PET-CT imaging demonstrates residual tumor and low nonspecific uptake in the resection site. We conclude that (64)Cu-DOTA-cetuximab-F(ab´)2 binds specifically to intracranial EGFR WT and EGFRvIII expressing GBM, demonstrates excellent TBR, and specifically images small residual tumor in a surgical model, suggesting future clinical utility in identifying true tumor recurrence.


Continuous nicotine exposure does not affect resurgence of alcohol seeking in rats.
Alcohol is the most commonly used drug in the United States and alcohol abuse can lead to alcohol use disorder. Alcohol use disorder is a persistent condition and relapse rates following successful remission are high. Many factors have been associated with relapse for alcohol use disorder, but identification of these factors has not been well translated into preventative utility. One potentially important factor, concurrent nicotine use, has not been well investigated as a causal factor in relapse for alcohol use disorder. Nicotine increases the value of other stimuli in the environment and may increase the value of alcohol. If nicotine increases the value of alcohol, then nicotine use during and after treatment may make relapse more probable. In the current study, we investigated the effect of continuous nicotine exposure (using osmotic minipumps to deliver nicotine or saline, depending on group, at a constant rate for 28 days) on resurgence of alcohol seeking in rats. Resurgence is a type of relapse preparation that consists of three phases: Baseline, Alternative Reinforcement, and Resurgence Testing. During Baseline, target responses produced a dipper of alcohol. During Alternative Reinforcement, target responses were extinguished and responses on a chain produced a chocolate pellet. During Resurgence Testing, responses on the chain were also extinguished and a return to responding on the target lever was indicative of resurgence. Multilevel modeling was used to analyze the effect of nicotine on resurgence. Both the nicotine and saline group showed resurgence of alcohol seeking, but there was no difference in the degree of resurgence across groups. Future directions could involve testing alternative drug delivery techniques.


Uncovering pseudotemporal trajectories with covariates from single cell and bulk expression data.
Pseudotime algorithms can be employed to extract latent temporal information from cross-sectional data sets allowing dynamic biological processes to be studied in situations where the collection of time series data is challenging or prohibitive. Computational techniques have arisen from single-cell 'omics and cancer modelling where pseudotime can be used to learn about cellular differentiation or tumour progression. However, methods to date typically implicitly assume homogeneous genetic, phenotypic or environmental backgrounds, which becomes limiting as data sets grow in size and complexity. We describe a novel statistical framework that learns how pseudotime trajectories can be modulated through covariates that encode such factors. We apply this model to both single-cell and bulk gene expression data sets and show that the approach can recover known and novel covariate-pseudotime interaction effects. This hybrid regression-latent variable model framework extends pseudotemporal modelling from its most prevalent area of single cell genomics to wider applications.


Loss of skeletal mineralization by the simultaneous ablation of PHOSPHO1 and alkaline phosphatase function: a unified model of the mechanisms of initiation of skeletal calcification.
Endochondral ossification is a carefully orchestrated process mediated by promoters and inhibitors of mineralization. Phosphatases are implicated, but their identities and functions remain unclear. Alkaline phosphatase (TNAP) plays a crucial role promoting mineralization of the extracellular matrix by restricting the concentration of the calcification inhibitor inorganic pyrophosphate (PP(i)). Mutations in the TNAP gene cause hypophosphatasia, a heritable form of rickets and osteomalacia. Here we show that PHOSPHO1, a phosphatase with specificity for phosphoethanolamine and phosphocholine, plays a functional role in the initiation of calcification and that ablation of PHOSPHO1 and TNAP function prevents skeletal mineralization. Phospho1(-/-) mice display growth plate abnormalities, spontaneous fractures, bowed long bones, osteomalacia, and scoliosis in early life. Primary cultures of Phospho1(-/-) tibial growth plate chondrocytes and chondrocyte-derived matrix vesicles (MVs) show reduced mineralizing ability, and plasma samples from Phospho1(-/-) mice show reduced levels of TNAP and elevated plasma PP(i) concentrations. However, transgenic overexpression of TNAP does not correct the bone phenotype in Phospho1(-/-) mice despite normalization of their plasma PP(i) levels. In contrast, double ablation of PHOSPHO1 and TNAP function leads to the complete absence of skeletal mineralization and perinatal lethality. We conclude that PHOSPHO1 has a nonredundant functional role during endochondral ossification, and based on these data and a review of the current literature, we propose an inclusive model of skeletal calcification that involves intravesicular PHOSPHO1 function and P(i) influx into MVs in the initiation of mineralization and the functions of TNAP, nucleotide pyrophosphatase phosphodiesterase-1, and collagen in the extravesicular progression of mineralization.


Legume diversity patterns in West Central Africa: influence of species biology on distribution models.
Species Distribution Models (SDMs) are used to produce predictions of potential Leguminosae diversity in West Central Africa. Those predictions are evaluated subsequently using expert opinion. The established methodology of combining all SDMs is refined to assess species diversity within five defined vegetation types. Potential species diversity is thus predicted for each vegetation type respectively. The primary aim of the new methodology is to define, in more detail, areas of species richness for conservation planning. Using Maxent, SDMs based on a suite of 14 environmental predictors were generated for 185 West Central African Leguminosae species, each categorised according to one of five vegetation types: Afromontane, coastal, non-flooded forest, open formations, or riverine forest. The relative contribution of each environmental variable was compared between different vegetation types using a nonparametric Kruskal-Wallis analysis followed by a post-hoc Kruskal-Wallis Paired Comparison contrast. Legume species diversity patterns were explored initially using the typical method of stacking all SDMs. Subsequently, five different ensemble models were generated by partitioning SDMs according to vegetation category. Ecological modelers worked with legume specialists to improve data integrity and integrate expert opinion in the interpretation of individual species models and potential species richness predictions for different vegetation types. Of the 14 environmental predictors used, five showed no difference in their relative contribution to the different vegetation models. Of the nine discriminating variables, the majority were related to temperature variation. The set of variables that played a major role in the Afromontane species diversity model differed significantly from the sets of variables of greatest relative important in other vegetation categories. The traditional approach of stacking all SDMs indicated overall centers of diversity in the region but the maps indicating potential species richness by vegetation type offered more detailed information on which conservation efforts can be focused.


Effect of aqueous tobacco smoke extract and shear stress on PECAM-1 expression and cell motility in human uterine endothelial cells.
Tobacco smoke constituents have several adverse effects on endothelial cells. Exposure to tobacco smoke during pregnancy is associated with adverse effects on pregnancy outcome possibly related to endothelial dysfunction. Platelet endothelial cell adhesion molecule-1 (PECAM-1) is an important regulator of endothelial function. This study tests the idea that an aqueous extract of cigarette smoke alters the expression of PECAM-1 in uterine endothelial cells. Human uterine microvascular endothelial cells were cultured in cigarette smoke-conditioned medium (CSM) under arterial physiological flow conditions (shear or frictional stress in the range 7.5-15 dyne/cm(2)) and the expression of PECAM-1 was assessed by immunofluorescence microscopy and Western blotting. Thick reticular PECAM-1-associated bands found at cell-cell junctions in static cultures became significantly thinner or disappeared when the cells were exposed to shear stress or to CSM for 24 h. This diminution at cell junctions was accompanied by increased punctate cytoplasmic/cell surface staining. Under shear stress conditions, PECAM-1 was equally distributed between cell surface and intracellular sites. In contrast, when cells were exposed to both shear stress and CSM, PECAM-1 was predominantly localized to the cell surface. It was shown that shear stress increased endothelial cell migration and that CSM abrogated this effect. These results suggest that, under shear stress conditions, PECAM-1 is not predominantly concentrated at intercellular junctions in uterine endothelial cells. Exposure of cells to unidentified soluble components of cigarette smoke leads to alterations in PECAM-1 distribution that may cause endothelial dysfunction. If this occurs in vivo it could contribute to the adverse effects on pregnancy outcome associated with exposure to cigarette smoke.


Dust exposure and chronic respiratory symptoms among coffee curing workers in Kilimanjaro: a cross sectional study.
Coffee processing causes organic dust exposure which may lead to development of respiratory symptoms. Previous studies have mainly focused on workers involved in roasting coffee in importing countries. This study was carried out to determine total dust exposure and respiratory health of workers in Tanzanian primary coffee-processing factories. A cross sectional study was conducted among 79 workers in two coffee factories, and among 73 control workers in a beverage factory. Personal samples of total dust (n = 45 from the coffee factories and n = 19 from the control factory) were collected throughout the working shift from the breathing zone of the workers. A questionnaire with modified questions from the American Thoracic Society questionnaire was used to assess chronic respiratory symptoms. Differences between groups were tested by using independent t-tests and Chi square tests. Poisson Regression Model was used to estimate prevalence ratio, adjusting for age, smoking, presence of previous lung diseases and years worked in dusty factories. All participants were male. The coffee workers had a mean age of 40 years and were older than the controls (31 years). Personal total dust exposure in the coffee factories were significantly higher than in the control factory (geometric mean (GM) 1.23 mg/m3, geometric standard deviation (GSD) (0.8) vs. 0.21(2.4) mg/m3). Coffee workers had significantly higher prevalence than controls for cough with sputum (23% vs. 10%; Prevalence ratio (PR); 2.5, 95% CI 1.0-5.9) and chest tightness (27% vs. 13%; PR; 2.4, 95% CI 1.1-5.2). The prevalence of morning cough, cough with and without sputum for 4 days or more in a week was also higher among coffee workers than among controls. However, these differences were not statistically significant. Workers exposed to coffee dust reported more respiratory symptoms than did the controls. This might relate to their exposure to coffee dust. Interventions for reduction of dust levels and provision of respiratory protective equipment are recommended.


Hypoxic/ischemic and infectious events have cumulative effects on the risk of cerebral palsy in very-low-birth-weight preterm infants.
Hypoxia/ischemia and inflammation are two major mechanisms for cerebral palsy (CP) in preterm infants. To investigate whether hypoxia/ischemia- and infection-related events in the perinatal and neonatal periods had cumulative effects on CP risk in very-low-birth-weight (VLBW) premature infants. From 1995 to 2005, 5,807 VLBW preterm infants admitted to Taiwan hospitals were enrolled. The cumulative effects of hypoxic/ischemic and infectious events during the perinatal and neonatal periods on CP risk at corrected age 24 months were analyzed. Of the 4,355 infants with 24-month follow-up, 457 (10.5%) had CP. The CP group had significantly higher incidences of hypoxia/ischemia-related events in the perinatal and neonatal periods, and sepsis in the neonatal period than the normal group. Three hypoxic/ischemic events, including birth cardiopulmonary resuscitation (OR 2.25; 95% CI 1.81-2.82), patent ductus arteriosus (PDA) ligation (2.94; 1.35-5.75) and chronic lung disease (3.14; 2.61-3.85) had the most significant contribution to CP. Relative to CP risk for infants with neither the three hypoxic/ischemic events nor sepsis, the CP odds increased 1.98-, 2.26- and 2.15-fold for infants with birth cardiopulmonary resuscitation, PDA ligation and chronic lung disease, respectively; while the combination with sepsis further increased the odds to 3.18-, 3.83- and 3.25-fold, respectively. Using the three hypoxic/ischemic events plus sepsis, CP rates were 10.0, 16.7, 26.7, 40.0 and 54.7% for infants with none, one, two, three and four events, respectively. Hypoxic/ischemic and infectious events across the perinatal and neonatal periods exerted cumulative effects on CP risk in VLBW premature infants.


Changes in function of HIV-specific T-cell responses with increasing time from infection.
Recently HIV-infected individuals have virus-specific responses characterized by IFN-gamma/IL-2 secretion and proliferation rarely seen in chronic infection. To investigate the timing of loss of HIV-specific T-cell function, we screened cells from 59 treatment-naïve HIV-infected individuals with known dates of infection for proteome-wide responses secreting IFN-gamma/IL-2 and IFN-gamma alone by ELISPOT. HIV peptide-specific proliferation was assessed by carboxyfluorescein diacetate succinimidyl ester (CFSE) dilution. The contribution of IFN-gamma/IL-2 and IFN-gamma-only secretion to the total HIV-specific response was compared in subjects infected <6, 6-12, and 12-36 mo earlier. The frequency of IFN-gamma/IL-2-secreting cells fell, while that of IFN-gamma-only secretion rose with time from infection. HIV peptide-specific proliferative responses were almost exclusively mediated by CD8(+) T cells, and were significantly lower in cells obtained from the 12-36 mo versus < 6 mo post-infection groups. By the second year of infection there was a significant difference in these functions compared to those assessed within 6 mo.


The COP9 signalosome is required for autophagy, proteasome-mediated proteolysis, and cardiomyocyte survival in adult mice.
The COP9 signalosome (CSN) is an evolutionarily conserved protein complex composed of 8 unique protein subunits (CSN1 through CSN8). We have recently discovered in perinatal mouse hearts that CSN regulates not only proteasome-mediated proteolysis but also macroautophagy. However, the physiological significance of CSN in a post-mitotic organ of adult vertebrates has not been determined. We sought to study the physiological role of CSN8/CSN in adult mouse hearts. Csn8 was conditionally ablated in the cardiomyocytes of adult mice (CSN8(CKO)) using a temporally controlled Cre-LoxP system. Loss of CSN8 accumulated the neddylated forms of cullins and noncullin proteins, increased ubiquitinated proteins, and stabilized a surrogate substrate of the proteasome in the heart. Autophagic flux was significantly decreased, whereas autophagosomes were markedly increased in CSN8(CKO) hearts, indicative of impaired autophagosome removal. Furthermore, we observed increased oxidized proteins, massive necrotic cardiomyocytes, and morphological and functional changes characteristic of dilated cardiomyopathy in CSN8(CKO) mice. CSN deneddylates substrates more than cullins and is indispensable to cardiomyocyte survival in not only perinatal hearts but also adult hearts. CSN8/CSN regulates both proteasome-mediated proteolysis and the autophagic-lysosomal pathway, critical to the removal of oxidized proteins in the heart.


Urinary excretion of factor VIII after renal transplantation.
The urinary excretion of factor-VIII-related antigen (VIIIRAg) was measured in 72 patients with kidney transplants and compared with that of two end-products of fibrin-fibrinogen lysis (fragments D and E) to assess their usefulness in monitoring the onset of rejection episodes. Specific and sensitive radioimmunoassays were used to measure the three proteins. Unconcentrated urine samples of 24-hour collections were obtained from 20 healthy subjects, 48 patients with stable transplants, and 24 patients with recent transplants serially followed up from the day of transplantation. Factor VIIIRAg and fragments E and D were not detectable in the urine from healthy subjects but were present in 39%, 60%, and 100% respectively of samples from patients with stable transplants. During 33 acute rejection episodes in 19 patients with recent transplants factor VIIIRAg and fragments E and D were significantly increased above the values observed in patients with stable transplants in 82%, 73%, and 64% of samples respectively; in patients with recent transplants showing no clinical sign of rejection increased excretion of these proteins was observed in 11%, 26%, and 22% of samples respectively. The presence of factor VIIIRAg in urine from patients with kidney allografts suggests that endothelial cell-factor VIII-platelet interactions might pay a key part in the pathogenesis of acute rejection. The results suggest that the assay of factor VIIIRAg in urine is more useful than assays of fragments D and E as a corroborative index of transplant rejection.


Patellofemoral Pain After Total Knee Arthroplasty.
The incidence of patellofemoral complications after total knee arthroplasty has been reported to range from 2% to 7%. Such complications include pain, sub-luxation, dislocation, loosening, and wear. Usually these complications are attrib-utable to prosthetic design or surgical technique. Today, it is understood that patellofemoral prostheses must have a degree of congruence; must allow smooth, not abrupt, motion; and must restore a relatively normal size relationship between the patella and the femur. Surgical technique requires strict attention to (1) restoration of the patellofemoral spacing while avoiding "overstuffing" of the patellofemoral compartment; (2) accurate superior and medial positioning of the patellar component; (3) restoration of the rotational alignment of the femoral and tibial components; and (4) appropriate balancing of the patellofemoral soft tissues.


Dictated versus database-generated discharge summaries: a randomized clinical trial.
Hospital discharge summaries communicate information necessary for continuing patient care. They are most commonly generated by voice dictation and are often of poor quality. The objective of this study was to compare discharge summaries created by voice dictation with those generated from a clinical database. A randomized clinical trial was performed in which discharge summaries for patients discharged from a general internal medicine service at a tertiary care teaching hospital in Ottawa were created by voice dictation (151 patients) or from a database (142 patients). Patients had been admitted between September 1996 and June 1997. The trial was preceded by a baseline cohort study in which all summaries were created by dictation. For the database group, information on forms completed by housestaff was entered into a database and collated into a discharge summary. For the dictation group, housestaff dictated narrative letters. The proportion of patients for whom a summary was generated within 4 weeks of discharge was recorded. Physicians receiving the summary rated its quality, completeness, organization and timeliness on a 100-mm visual analogue scale. Housestaff preference was also determined. Patients in the database group and the dictation group were similar. A summary was much more likely to be generated within 4 weeks of discharge for patients in the database group than for those in the dictation group (113 [79.6%] v. 86 [57.0%]; p < 0.001). Summary quality was similar (mean rating 72.7 [standard deviation (SD) 19.3] v. 74.9 [SD 16.6]), as were assessments of completeness (73.4 [SD 19.8] v. 78.2 [SD 14.9]), organization (77.4 [SD 16.3] v. 79.3 [SD 17.2]) and timeliness (70.3 [SD 21.9] v. 66.2 [SD 25.6]). Many information items of interest were more likely to be included in the database-generated summaries. The database system created summaries faster and was preferred by housestaff. Dictated summaries in the baseline and randomized studies were similar, which indicated that the control group was not substantially different from the baseline cohort. The database system significantly increased the likelihood that a discharge summary was created. Housestaff preferred the database system for summary generation. Physicians thought that the quality of summaries generated by the 2 methods was similar. The use of computer databases to create hospital discharge summaries is promising and merits further study and refinement.


18-Methoxycoronaridine blocks acquisition but enhances reinstatement of a cocaine place preference.
The iboga alkaloid congener, 18-methoxycoronaridine (18-MC), decreases self-administration of multiple drugs of abuse. Here, in a biased procedure, we investigated whether 18-MC would have a similar effect on the acquisition, expression and reinstatement of a cocaine conditioned place preference (CPP) in male Sprague-Dawley rats. While 18-MC attenuated acquisition of a cocaine CPP, it had no effect on CPP expression, and enhanced the reinstatement of cocaine CPP following extinction. Our results are consistent with those obtained using ibogaine, but reinforce the notion that acquisition, expression and reinstatement of a CPP likely involve separate mechanisms.


Newborn Sequencing in Genomic Medicine and Public Health.
The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.


Movement-related cortical potentials in paraplegic patients: abnormal patterns and considerations for BCI-rehabilitation.
Non-invasive EEG-based Brain-Computer Interfaces (BCI) can be promising for the motor neuro-rehabilitation of paraplegic patients. However, this shall require detailed knowledge of the abnormalities in the EEG signatures of paraplegic patients. The association of abnormalities in different subgroups of patients and their relation to the sensorimotor integration are relevant for the design, implementation and use of BCI systems in patient populations. This study explores the patterns of abnormalities of movement related cortical potentials (MRCP) during motor imagery tasks of feet and right hand in patients with paraplegia (including the subgroups with/without central neuropathic pain (CNP) and complete/incomplete injury patients) and the level of distinctiveness of abnormalities in these groups using pattern classification. The most notable observed abnormalities were the amplified execution negativity and its slower rebound in the patient group. The potential underlying mechanisms behind these changes and other minor dissimilarities in patients' subgroups, as well as the relevance to BCI applications, are discussed. The findings are of interest from a neurological perspective as well as for BCI-assisted neuro-rehabilitation and therapy.


Myricetin inhibits angiotensin converting enzyme and induces nitric oxide production in HUVEC cell line.
Nitric oxide is known as relaxing factor because it acts as a vasodilator, increases blood flow, and inhibits platelet aggregation and adhesion, on the other hand nitric oxide can modulate cellular and physiological processes to limit oxidative injury, limiting processes such as leukocyte adhesion. As the complete mechanism of myricetin and its cardiovascular benefits is not completely understood, the aim of this study was to investigate the antihypertensive activity of myricetin in human umbilical vein endothelial cell (HUVEC). Angiotensin converting enzyme (ACE) activity, nitric oxide production, reactive oxygen species (ROS) scavenger activity, cellular calcium concentration, and endothelial nitric oxide synthase (eNOS) activity and protein expression was investigated in HUVEC treated with different concentration of myricetin (1-60 µM). Myricetin increased nitric oxide production in HUVEC through decreased ROS levels and increased nitric oxide production and eNOS activation. Activation of eNOS enzyme was achieved by an increase of cellular calcium concentration. At the same examined concentration of myricetin, the activity of ACE was significantly inhibited. These findings indicate that myricetin may be helpful for lowering blood pressure; this could be achieved through dietary intervention or by the production of new antihypertensive treatments from a natural product.


n-3 fatty acids and rosiglitazone improve insulin sensitivity through additive stimulatory effects on muscle glycogen synthesis in mice fed a high-fat diet.
Fatty acids of marine origin, i.e. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) act as hypolipidaemics, but they do not improve glycaemic control in obese and diabetic patients. Thiazolidinediones like rosiglitazone are specific activators of peroxisome proliferator-activated receptor gamma, which improve whole-body insulin sensitivity. We hypothesised that a combined treatment with a DHA and EPA concentrate (DHA/EPA) and rosiglitazone would correct, by complementary additive mechanisms, impairments of lipid and glucose homeostasis in obesity. Male C57BL/6 mice were fed a corn oil-based high-fat diet. The effects of DHA/EPA (replacing 15% dietary lipids), rosiglitazone (10 mg/kg diet) or a combination of both on body weight, adiposity, metabolic markers and adiponectin in plasma, as well as on liver and muscle gene expression and metabolism were analysed. Euglycaemic-hyperinsulinaemic clamps were used to characterise the changes in insulin sensitivity. The effects of the treatments were also analysed in dietary obese mice with impaired glucose tolerance (IGT). DHA/EPA and rosiglitazone exerted additive effects in prevention of obesity, adipocyte hypertrophy, low-grade adipose tissue inflammation, dyslipidaemia and insulin resistance, while inducing adiponectin, suppressing hepatic lipogenesis and decreasing muscle ceramide concentration. The improvement in glucose tolerance reflected a synergistic stimulatory effect of the combined treatment on muscle glycogen synthesis and its sensitivity to insulin. The combination treatment also reversed dietary obesity, dyslipidaemia and IGT. DHA/EPA and rosiglitazone can be used as complementary therapies to counteract dyslipidaemia and insulin resistance. The combination treatment may reduce dose requirements and hence the incidence of adverse side effects of thiazolidinedione therapy.


Rasip1 controls lymphatic vessel lumen maintenance by regulating endothelial cell junctions.
Although major progress in our understanding of the genes and mechanisms that regulate lymphatic vasculature development has been made, we still do not know how lumen formation and maintenance occurs. Here, we identify the Ras-interacting protein Rasip1 as a key player in this process. We show that lymphatic endothelial cell-specific Rasip1-deficient mouse embryos exhibit enlarged and blood-filled lymphatics at embryonic day 14.5. These vessels have patent lumens with disorganized junctions. Later on, as those vessels become fragmented and lumens collapse, cell junctions become irregular. In addition, Rasip1 deletion at later stages impairs lymphatic valve formation. We determined that Rasip1 is essential for lymphatic lumen maintenance during embryonic development by regulating junction integrity, as Rasip1 loss results in reduced levels of junction molecules and defective cytoskeleton organization in vitro and in vivo We determined that Rasip1 regulates Cdc42 activity, as deletion of Cdc42 results in similar phenotypes to those seen following the loss of Rasip1 Furthermore, ectopic Cdc42 expression rescues the phenotypes in Rasip1-deficient lymphatic endothelial cells, supporting the suggestion that Rasip1 regulates Cdc42 activity to regulate cell junctions and cytoskeleton organization, which are both activities required for lymphatic lumen maintenance.


Effect of different cleaning methods of polyetheretherketone on surface roughness and surface free energy properties.
To determine the effect of different individual, laboratory and professional cleaning methods on the surface-roughness (SR) and surface free energy (SFE) of polyetheretherketone (PEEK), PMMA-based (PMMA) and composite (COMP) materials. 330 specimens of PEEK, PMMA and COMP (N = 990) were prepared and divided into the following cleaning protocols (n = 30/group): (i) individual prophylaxis using (ST) soft, (MT) medium-hard and (SOT) sonic toothbrushes, (ii) in-lab cleaning protocols consisting of (SY) Sympro cleaning system, (SS) SunSparkle, (UB) ultrasonic bath and (AP) Al2O3-powder device and (iii) professional prophylaxis applying (PS) Perio Soft-Scaler, (SO) Sonicsys, (AFC) Air Flow Comfort, and (AFP) Air Flow Plus. After each protocol SR (profilometer), SFE (contact angle devise) and surface topography (SEM) were measured. Data were analyzed using multivariate analysis, Kruskal-Wallis-H- and Mann-Whitney-U-test (p<0.05). No impact of material on SR was observed (p = 0.443). Cleaning using conventional air-abrasion and powders (AP), followed by AFC produced higher SR values than the remaining methods (p<0.001). Within SFE, the cleaning method exerted the highest influence on SFE values (p<0.001, ηP2 = 0.246), closely followed by the polymer material (p<0.001, ηP2 = 0.136). PMMA and PEEK presented after cleaning lower SFE than COMP. PS, UB and SO showed lower SFE than specimens cleaned using SS, ST and SY. Cleaning using SY led to the highest SFE. With regard to SR, all methods - with exception of conventional air-abrasion - can be recommended to clean PEEK. According to the SFE, PEEK may be an acceptable material providing even lower plaque accumulation rates than COMP. The field for more research is now open for scrutiny.


Challenges in Translating PrEP Interest Into Uptake in an Observational Study of Young Black MSM.
HIV incidence among US young, black men who have sex with men (YBMSM) is high, and structural barriers (eg lack of health insurance) may limit access to Pre-exposure prophylaxis (PrEP). Research studies conducted with YBMSM must ensure access to the best available HIV prevention methods, including PrEP. We implemented an optional, nonincentivized PrEP program in addition to the standard HIV prevention services in a prospective, observational cohort of HIV-negative YBMSM in Atlanta, GA. Provider visits and laboratory costs were covered; participant insurance plans and/or the manufacturer assistance program were used to obtain drugs. Factors associated with PrEP initiation were assessed with prevalence ratios and time to PrEP initiation with Kaplan-Meier methods. Of 192 enrolled YBMSM, 4% were taking PrEP at study entry. Of 184 eligible men, 63% indicated interest in initiating PrEP, 10% reported no PrEP interest, and 27% wanted to discuss PrEP again at a future study visit. Of 116 interested men, 46% have not attended a PrEP initiation appointment. Sixty-three men (63/184; 34%) initiated PrEP; 11/63 (17%) subsequently discontinued PrEP. The only factor associated with PrEP initiation was reported sexually transmitted infection in the previous year (prevalence ratio 1.50, 95% confidence interval: 1.002 to 2.25). Among interested men, median time to PrEP initiation was 16 weeks (95% confidence interval: 7 to 36). Despite high levels of interest, PrEP uptake may be suboptimal among YBMSM in our cohort even with amelioration of structural barriers that can limit use. PrEP implementation as the standard of HIV prevention care in observational studies is feasible; however, further research is needed to optimize uptake for YBMSM.


Major histocompatibility complex heterozygosity enhances reproductive success.
We investigated how heterozygosity at the major histocompatibility complex (MHC) affects fitness in wild-derived (F2) house mice (Mus musculus musculus). To compare and control for potential confounding effects from close inbreeding and genome-wide heterozygosity, we used mice that were systematically outbred. We assessed how heterozygosity at MHC and background loci (using 15 microsatellite markers on 11 different chromosomes) affects individual survival and reproductive success (RS) in large, semi-natural population enclosures. We found that overall heterozygosity significantly increased RS, and this correlation was entirely explained by heterozygosity at two MHC loci. Moreover, we found that the effects of MHC heterozygosity depend on the level of background heterozygosity, and the benefits of maximal MHC heterozygosity show a curvilinear effect with increasing background heterozygosity. The enhanced RS from MHC heterozygosity was not because of increased survival, and although MHC heterozygosity was correlated with body mass, body mass did not correlate with RS when heterozygosity is controlled. Breeders were more MHC heterozygous than nonbreeders for both sexes, indicating that MHC heterozygosity enhanced fecundity, mating success or both. Our results show that (i) MHC heterozygosity enhances fitness among wild, outbred as well as congenic laboratory mice; (ii) heterozygosity-fitness correlations can potentially be explained by a few loci, such as MHC; (iii) MHC heterozygosity can increase fitness, even without affecting survival, by increasing mating and RS; and (iv) MHC effects depend on background genes, and maximal MHC heterozygosity is most beneficial at intermediate or optimal levels of background heterozygosity.


The role of assessment packages for diagnostic consultations: A conversation analytic perspective.
This article reports a conversation analysis of assessment package consultations. Healthcare delivery packages belong to a highly structured mode of healthcare delivery, in which specific courses of healthcare interventions related to assessment and treatment are predefined, both as to timing and content. Assessment packages are widely used in an increasing number of medical specialities; however, there is a lack of knowledge about how packaged assessment influences the interaction between doctor and patient. In this study, we investigate the final consultation in assessment packages, which is when the final clarification of the patient's symptoms takes place. The primary data of the study were eight audio recordings of consultations, and the secondary data were ethnographic field descriptions. In most consultations, packaged assessment was a resource as it provided fast and efficient clarification. In most cases, clarification was treated as good news since it either confirmed the absence of a serious disease or resulted in a diagnosis leading to relevant treatment offers. However, in some cases, clarification was not perceived as good news. This was the case in consultations with patients whose goal was to leave the consultation with clarification in the form of a definite diagnosis, but who were not offered such clarification. These patients negotiated the outcome of the consultation by applying implicit and explicit pressure, which induced the doctors to disregard the boundaries of the package and offer the patient more tests. The study highlights some of the problems related to introducing narrow, specialized package assessment.


The choice is yours? How women with ovarian cancer make sense of treatment choices.
Much has been made of the need for cancer patients to be involved in choices about their treatments. We explore the different approaches to involvement described by women with ovarian cancer and consider why being invited to make a choice can sometimes seem inappropriate and untimely. Qualitative interviews were conducted in the UK with women with ovarian cancer. Interviews were audio tape recorded and transcribed for qualitative analysis. The interviews were collected as part of a broader study of experiences of ovarian cancer as part of the DIPEx (personal experiences of health and illness) project which runs a website featuring further analyses and video and audio clips from the interviews. Women did not always recall being involved in decisions -some felt there had been no 'real' decisions to make or said they preferred their medical team to decide on their behalf. Other women described asking questions and seeking second opinions but still 'going along with' their doctor's recommendation. A few women (including some of those who had felt unable to participate in decisions soon after their diagnosis) said that they had learnt enough to take control or make at least some of their own treatment decisions. The manner in which options were offered to women sometimes led to confusion and concern, especially if women felt the doctor was unwilling to express his or her own preference. Some worried that not accepting the doctor's advice would prejudice their future care. Patients and doctors are often uncertain how best to share in decisions about treatments. Being asked about their preferences can surprise or shock women. Clinicians need to explain about clinical uncertainty and how individual values and preferences may relate to treatment decisions. Presenting the rationale for choice can be difficult and even when well presented, women can be left feeling ill prepared, panicky and trying to second guess what they think the doctor 'really' wanted them to do. When patients are invited to make choices their clinicians need to explain about clinical uncertainty and how individual values and preferences may relate to treatment decisions. The options should be communicated in a clear manner, differences in opinion should be acknowledged and the doctor's own preference stated. Patients need to be encouraged and supported to make their decision-whether or not it reflects their doctor's preference. Patients should also be reassured that whichever decision they make their subsequent care and relationship with their medical team will not be adversely affected.


Piperlongumine induces apoptosis and autophagy in human lung cancer cells through inhibition of PI3K/Akt/mTOR pathway.
Piperlongumine (PL), a natural alkaloid present in the fruit of the Long pepper, is known to exhibit notable anti-cancer effects. Nonetheless, the anti-tumor effect of PL in lung cancer cells still remains unclear. In the present study, we reported the chemotherapeutic effects of PL using in vitro and in vivo models. We showed that PL displayed potent anti-neoplastic activity against lung cancer A549 cells as well as corresponding docetaxel-resistant A549/DTX cells. In addition, we found that PL induced apoptosis in both A549 and A549/DTX cells. PL also induced autophagy in A549/DTX cells. Moreover, autophagy-specific inhibitors (3-methyladenine) or Beclin1 and Atg 5 small interfering RNAs (siRNAs) enhanced PL-induced apoptosis, indicating that PL-mediated autophagy may protect A549/DTX cells from undergoing apoptotic cell death. Furthermore, we observed the inhibition of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway by PL. Finally, PL inhibited the growth of A549/DTX xenograft tumors, which was associated with inhibition of cell proliferation, induction of apoptosis of tumor cells and decreased expression of p-Akt and p-mTOR in tumor xenograft tissues. In summary, our study demonstrated that PL induced apoptosis and autophagy through modulation of the PI3K/Akt/mTOR pathway in human lung cancer cells. This study may provide a rationale for future clinical application using PL as a chemotherapeutic agent for lung cancer.


Resting-State Blood Oxygen Level-Dependent Functional MRI: A Paradigm Shift in Preoperative Brain Mapping.
Currently, functional magnetic resonance imaging (fMRI) facilitates a preoperative awareness of an association of an eloquent region with a tumor. This information gives the neurosurgeon helpful information that can aid in creating a surgical strategy. Typically, task-based fMRI has been employed to preoperatively localize speech and motor function. Task-based fMRI depends on the patient's ability to comply with the task paradigm, which often is impaired in the setting of a brain tumor. This problem is overcome by using resting-state fMRI (rs-fMRI) to localize function. rs-fMRI measures spontaneous fluctuations in the blood oxygen level-dependent (BOLD) signal, representing the brain's functional organization. In a neurosurgical context, it allows noninvasive simultaneous assessment of multiple large-scale distributed networks. Compared with task-related fMRI, rs-fMRI provides more comprehensive information on the functional architecture of the brain and is applicable in settings where task-related fMRI may provide inadequate information or could not be performed. Taken together, rs-fMRI substantially expands the preoperative mapping capability in efficiency, effectiveness, and scope. In this article, a brief introduction into rs-fMRI processing methods is followed by a detailed discussion on the role rs-fMRI plays in presurgical planning.


Avian P1 antigens inhibit agglutination mediated by P fimbriae of uropathogenic Escherichia coli.
Whole egg white from pigeon, dove, and cockatiel eggs, as well as the ovomucoid fraction of pigeon egg white, exhibited strong P1 antigenic activities and inhibited agglutination of human P1 erythrocytes and of digalactoside-coated latex beads by P-fimbriated Escherichia coli strains. In contrast, chicken egg white exhibited only weak P1 antigenic activity and had little impact on P-fimbrial agglutination. These preparations did not affect hemagglutination by E. coli strains expressing mannose-resistant adhesins other than P fimbriae, i.e., Dr, F1845, and S adhesins. Human anti-P1 serum diminished the P-fimbrial inhibitory activities of pigeon egg white and pigeon ovomucoid. Pigeon ovomucoid was equipotent on a molar basis with globoside, and the pigeon, dove, and cockatiel egg white preparations were equipotent with each other in P-fimbrial inhibition. Incubation of p erythrocytes in whole egg whites or in pigeon ovomucoid did not render them agglutinable by P-fimbriated bacteria, whereas incubation in globoside did. These data demonstrate that whole egg whites (and their ovomucoid fraction) from members of the families Columbidae (pigeons and doves) and Psittacidae (parrots) specifically and potently inhibit P-fimbrial agglutination, probably by providing P1 antigen as a receptor for the P-fimbrial adhesin. Avian egg white preparations may facilitate adhesin characterization of wild-type uropathogenic strains and may useful in preventing upper urinary tract infections due to P-fimbriated E. coli.


Transfer RNAs associated with vesicular stomatitis virus.
The predominant RNAs in purified VSV particles are 42S and 4S in size. The 4S RNA is host transfer RNA that did not incorporate detectable radiolabel during VSV infection and was detected by in vitro labelling. Surprisingly, when BHK cells were prelabelled for 30 to 54 h before infection, the incorporation of [3H]uridine and [32P]orthophosphate into virus tRNAs remained very low and virus tRNAs were found to have a 5- to 15-fold lower specific activity than the total host tRNA, the value depending, in part, upon the period of prelabelling. Two-dimensional gel electrophoresis and partial sequence analysis indicated that the virus tRNAs include most species of host tRNA and no singly predominant species was apparent. Transfer RNAs are packaged by several enveloped viruses, but we have not found 4S RNA in reovirus, which lacks an envelope. We suggest that VSV contains a membrane-associated population of tRNA which has a slower rate of turnover than the total population of cellular tRNA.