Measurements of Heart Rate and Accelerometry to Determine the Physical Activity Level in Boys Playing Paintball.
Paintball is a popular recreational sport played by 3.655 million Americans and may be sufficient physical activity to promote health. Paintball has been played as an organized sport since the 1980's and is essentially a game of tag, except instead of touching an opponent by hand opponents are tagged by shooting them with a paintball that leaves a mark indicating who has been eliminated. A previous evaluation of paintball as physical activity had 13 subjects undergo a VO2max test to develop a heart rate (HR) /oxygen consumption relationship, and it was observed that heart rates during paintball were 68-73% of the measured maximal HR. The present study used accelerometry and HR monitors to evaluate the quantity and intensity of physical activity in boys playing paintball. Eleven boys (12.7 ± 1.0 y, 51.5 ± 11.3 kg, 161.8 ± 10.1 cm) engaged in a VO2max test to develop a HR/oxygen consumption correlation. On a separate day the boys played 7 games of outdoor paintball while wearing a HR monitor and accelerometer. The boys played paintball for 11.5 ± 6.2 minutes/game for a total of 80.6 ± 10.0 minutes of game play. Average HR during paintball play was 129.6 ± 6.6 beats/min, representing 39.9 ± 12.9% VO2max. Based on accelerometry, the boys accumulated 63.2 ± 15.6 minutes of moderate intensity activity and 2.6 ± 2.8 minutes of vigorous activity during paintball. These data suggest that playing paintball may be considered as physical activity that is > 3 METs, and thus health promoting.


An examination of the psychometric structure of the Multidimensional Pain Inventory in temporomandibular disorder patients: a confirmatory factor analysis.
This paper seeks to analyse the psychometric and structural properties of the Multidimensional Pain Inventory (MPI) in a sample of temporomandibular disorder patients. The internal consistency of the scales was obtained. Confirmatory Factor Analysis was carried out to test the MPI structure section by section in a sample of 114 temporomandibular disorder patients. Nearly all scales obtained good reliability indexes. The original structure could not be totally confirmed. However, with a few adjustments we obtained a satisfactory structural model of the MPI which was slightly different from the original: certain items and the Self control scale were eliminated; in two cases, two original scales were grouped in one factor, Solicitous and Distracting responses on the one hand, and Social activities and Away from home activities, on the other. The MPI has been demonstrated to be a reliable tool for the assessment of pain in temporomandibular disorder patients. Some divergences to be taken into account have been clarified.


Action of octopamine and tyramine on muscles of Drosophila melanogaster larvae.
Octopamine (OA) and tyramine (TA) play important roles in homeostatic mechanisms, behavior, and modulation of neuromuscular junctions in arthropods. However, direct actions of these amines on muscle force production that are distinct from effects at the neuromuscular synapse have not been well studied. We utilize the technical benefits of the Drosophila larval preparation to distinguish the effects of OA and TA on the neuromuscular synapse from their effects on contractility of muscle cells. In contrast to the slight and often insignificant effects of TA, the action of OA was profound across all metrics assessed. We demonstrate that exogenous OA application decreases the input resistance of larval muscle fibers, increases the amplitude of excitatory junction potentials (EJPs), augments contraction force and duration, and at higher concentrations (10(-5) and 10(-4) M) affects muscle cells 12 and 13 more than muscle cells 6 and 7. Similarly, OA increases the force of synaptically driven contractions in a cell-specific manner. Moreover, such augmentation of contractile force persisted during direct muscle depolarization concurrent with synaptic block. OA elicited an even more profound effect on basal tonus. Application of 10(-5) M OA increased synaptically driven contractions by ≈ 1.1 mN but gave rise to a 28-mN increase in basal tonus in the absence of synaptic activation. Augmentation of basal tonus exceeded any physiological stimulation paradigm and can potentially be explained by changes in intramuscular protein mechanics. Thus we provide evidence for independent but complementary effects of OA on chemical synapses and muscle contractility.


How much time do nurses have for patients? A longitudinal study quantifying hospital nurses' patterns of task time distribution and interactions with health professionals.
Time nurses spend with patients is associated with improved patient outcomes, reduced errors, and patient and nurse satisfaction. Few studies have measured how nurses distribute their time across tasks. We aimed to quantify how nurses distribute their time across tasks, with patients, in individual tasks, and engagement with other health care providers; and how work patterns changed over a two year period. Prospective observational study of 57 nurses for 191.3 hours (109.8 hours in 2005/2006 and 81.5 in 2008), on two wards in a teaching hospital in Australia. The validated Work Observation Method by Activity Timing (WOMBAT) method was applied. Proportions of time in 10 categories of work, average time per task, time with patients and others, information tools used, and rates of interruptions and multi-tasking were calculated. Nurses spent 37.0%[95%CI: 34.5, 39.3] of their time with patients, which did not change in year 3 [35.7%; 95%CI: 33.3, 38.0]. Direct care, indirect care, medication tasks and professional communication together consumed 76.4% of nurses' time in year 1 and 81.0% in year 3. Time on direct and indirect care increased significantly (respectively 20.4% to 24.8%, P < 0.01;13.0% to 16.1%, P < 0.01). Proportion of time on medication tasks (19.0%) did not change. Time in professional communication declined (24.0% to 19.2%, P < 0.05). Nurses completed an average of 72.3 tasks per hour, with a mean task length of 55 seconds. Interruptions arose at an average rate of two per hour, but medication tasks incurred 27% of all interruptions. In 25% of medication tasks nurses multi-tasked. Between years 1 and 3 nurses spent more time alone, from 27.5%[95%CI 24.5, 30.6] to 39.4%[34.9, 43.9]. Time with health professionals other than nurses was low and did not change. Nurses spent around 37% of their time with patients which did not change. Work patterns were increasingly fragmented with rapid changes between tasks of short length. Interruptions were modest but their substantial over-representation among medication tasks raises potential safety concerns. There was no evidence of an increase in team-based, multi-disciplinary care. Over time nurses spent significantly less time talking with colleagues and more time alone.


A cross-biome synthesis of soil respiration and its determinants under simulated precipitation changes.
Soil respiration (Rs) is the second-largest terrestrial carbon (C) flux. Although Rs has been extensively studied across a broad range of biomes, there is surprisingly little consensus on how the spatiotemporal patterns of Rs will be altered in a warming climate with changing precipitation regimes. Here, we present a global synthesis Rs data from studies that have manipulated precipitation in the field by collating studies from 113 increased precipitation treatments, 91 decreased precipitation treatments, and 14 prolonged drought treatments. Our meta-analysis indicated that when the increased precipitation treatments were normalized to 28% above the ambient level, the soil moisture, Rs, and the temperature sensitivity (Q10) values increased by an average of 17%, 16%, and 6%, respectively, and the soil temperature decreased by -1.3%. The greatest increases in Rs and Q10 were observed in arid areas, and the stimulation rates decreased with increases in climate humidity. When the decreased precipitation treatments were normalized to 28% below the ambient level, the soil moisture and Rs values decreased by an average of -14% and -17%, respectively, and the soil temperature and Q10 values were not altered. The reductions in soil moisture tended to be greater in more humid areas. Prolonged drought without alterations in the amount of precipitation reduced the soil moisture and Rs by -12% and -6%, respectively, but did not alter Q10. Overall, our synthesis suggests that soil moisture and Rs tend to be more sensitive to increased precipitation in more arid areas and more responsive to decreased precipitation in more humid areas. The responses of Rs and Q10 were predominantly driven by precipitation-induced changes in the soil moisture, whereas changes in the soil temperature had limited impacts. Finally, our synthesis of prolonged drought experiments also emphasizes the importance of the timing and frequency of precipitation events on ecosystem C cycles. Given these findings, we urge future studies to focus on manipulating the frequency, intensity, and seasonality of precipitation with an aim to improving our ability to predict and model feedback between Rs and climate change.


Study Protocol: The Heart and Brain Study.
It is well-established that what is good for the heart is good for the brain. Vascular factors such as hypertension, diabetes, and high cholesterol, and genetic factors such as the apolipoprotein E4 allele increase the risk of developing both cardiovascular disease and dementia. However, the mechanisms underlying the heart-brain association remain unclear. Recent evidence suggests that impairments in vascular phenotypes and cerebrovascular reactivity (CVR) may play an important role in cognitive decline. The Heart and Brain Study combines state-of-the-art vascular ultrasound, cerebrovascular magnetic resonance imaging (MRI) and cognitive testing in participants of the long-running Whitehall II Imaging cohort to examine these processes together. This paper describes the study protocol, data pre-processing and overarching objectives. The 775 participants of the Whitehall II Imaging cohort, aged 65 years or older in 2019, have received clinical and vascular risk assessments at 5-year-intervals since 1985, as well as a 3T brain MRI scan and neuropsychological tests between 2012 and 2016 (Whitehall II Wave MRI-1). Approximately 25% of this cohort are selected for the Heart and Brain Study, which involves a single testing session at the University of Oxford (Wave MRI-2). Between 2019 and 2023, participants will undergo ultrasound scans of the ascending aorta and common carotid arteries, measures of central and peripheral blood pressure, and 3T MRI scans to measure CVR in response to 5% carbon dioxide in air, vessel-selective cerebral blood flow (CBF), and cerebrovascular lesions. The structural and diffusion MRI scans and neuropsychological battery conducted at Wave MRI-1 will also be repeated. Using this extensive life-course data, the Heart and Brain Study will examine how 30-year trajectories of vascular risk throughout midlife (40-70 years) affect vascular phenotypes, cerebrovascular health, longitudinal brain atrophy and cognitive decline at older ages. The study will generate one of the most comprehensive datasets to examine the longitudinal determinants of the heart-brain association. It will evaluate novel physiological processes in order to describe the optimal window for managing vascular risk in order to delay cognitive decline. Ultimately, the Heart and Brain Study will inform strategies to identify at-risk individuals for targeted interventions to prevent or delay dementia.


Nutraceutical approach for the management of cardiovascular risk - a combination containing the probiotic Bifidobacterium longum BB536 and red yeast rice extract: results from a randomized, double-blind, placebo-controlled study.
Probiotics incorporated into dairy products have been shown to reduce total (TC) and LDL cholesterolemia (LDL-C) in subjects with moderate hypercholesterolemia. More specifically, probiotics with high biliary salt hydrolase activity, e.g. Bifidobacterium longum BB536, may decrease TC and LDL-C by lowering intestinal cholesterol reabsorption and, combined with other nutraceuticals, may be useful to manage hypercholesterolemia in subjects with low cardiovascular (CV) risk. This study was conducted to evaluate the efficacy and safety of a nutraceutical combination containing Bifidobacterium longum BB536, red yeast rice (RYR) extract (10 mg/day monacolin K), niacin, coenzyme Q10 (Lactoflorene Colesterolo®). The end-points were changes of lipid CV risk markers (LDL-C, TC, non-HDL-cholesterol (HDL-C), triglycerides (TG), apolipoprotein B (ApoB), HDL-C, apolipoprotein AI (ApoAI), lipoprotein(a) (Lp(a), proprotein convertase subtilisin/kexin type 9 (PCSK9)), and of markers of cholesterol synthesis/absorption. A 12-week randomized, parallel, double-blind, placebo-controlled study. Thirty-three subjects (18-70 years) in primary CV prevention and low CV risk (SCORE: 0-1% in 24 and 2-4% in 9 subjects; LDL-C: 130-200 mg/dL) were randomly allocated to either nutraceutical (N = 16) or placebo (N = 17). Twelve-week treatment with the nutraceutical combination, compared to placebo, significantly reduced TC (- 16.7%), LDL-C (- 25.7%), non-HDL-C (- 24%) (all p < 0.0001), apoB (- 17%, p = 0.003). TG, HDL-C, apoAI, Lp(a), PCSK9 were unchanged. Lathosterol:TC ratio was significantly reduced by the nutraceutical combination, while campesterol:TC ratio and sitosterol:TC ratio did not change, suggesting reduction of synthesis without increased absorption of cholesterol. No adverse effects and a 97% compliance were observed. A 12-week treatment with a nutraceutical combination containing the probiotic Bifidobacterium longum BB536 and RYR extract significantly improved the atherogenic lipid profile and was well tolerated by low CV risk subjects. NCT02689934 .


Reliability, validity, and sensitivity to change of the lower extremity functional scale in individuals affected by stroke.
To investigate reliability, validity, and sensitivity to change of the Lower Extremity Functional Scale (LEFS) in individuals affected by stroke. The secondary objective was to test the validity and sensitivity of a single-item linear analog scale (LAS) of function. Prospective cohort reliability and validation study. A single rehabilitation department in an academic medical center. Forty-three individuals receiving neurorehabilitation for lower extremity dysfunction after stroke were studied. Their ages ranged from 32 to 95 years, with a mean of 70 years; 77% were men. Test-retest reliability was assessed by calculating the classical intraclass correlation coefficient, and the Bland-Altman limits of agreement. Validity was assessed by calculating the Pearson correlation coefficient between the instruments. Sensitivity to change was assessed by comparing baseline scores with end of treatment scores. Measurements were taken at baseline, after 1-3 days, and at 4 and 8 weeks. The LEFS, Short-Form-36 Physical Function Scale, Berg Balance Scale, Six-Minute Walk Test, Five-Meter Walk Test, Timed Up-and-Go test, and the LAS of function were used. The test-retest reliability of the LEFS was found to be excellent (ICC = 0.96). Correlated with the 6 other measures of function studied, the validity of the LEFS was found to be moderate to high (r = 0.40-0.71). Regarding the sensitivity to change, the mean LEFS scores from baseline to study end increased 1.2 SD and for LAS 1.1 SD. LEFS exhibits good reliability, validity, and sensitivity to change in patients with lower extremity impairments secondary to stroke. Therefore, the LEFS can be a clinically efficient outcome measure in the rehabilitation of patients with subacute stroke. The LAS is shown to be a time-saving and reasonable option to track changes in a patient's functional status.


Generalisable long COVID subtypes: findings from the NIH N3C and RECOVER programmes.
Stratification of patients with post-acute sequelae of SARS-CoV-2 infection (PASC, or long COVID) would allow precision clinical management strategies. However, long COVID is incompletely understood and characterised by a wide range of manifestations that are difficult to analyse computationally. Additionally, the generalisability of machine learning classification of COVID-19 clinical outcomes has rarely been tested. We present a method for computationally modelling PASC phenotype data based on electronic healthcare records (EHRs) and for assessing pairwise phenotypic similarity between patients using semantic similarity. Our approach defines a nonlinear similarity function that maps from a feature space of phenotypic abnormalities to a matrix of pairwise patient similarity that can be clustered using unsupervised machine learning. We found six clusters of PASC patients, each with distinct profiles of phenotypic abnormalities, including clusters with distinct pulmonary, neuropsychiatric, and cardiovascular abnormalities, and a cluster associated with broad, severe manifestations and increased mortality. There was significant association of cluster membership with a range of pre-existing conditions and measures of severity during acute COVID-19. We assigned new patients from other healthcare centres to clusters by maximum semantic similarity to the original patients, and showed that the clusters were generalisable across different hospital systems. The increased mortality rate originally identified in one cluster was consistently observed in patients assigned to that cluster in other hospital systems. Semantic phenotypic clustering provides a foundation for assigning patients to stratified subgroups for natural history or therapy studies on PASC. NIH (TR002306/OT2HL161847-01/OD011883/HG010860), U.S.D.O.E. (DE-AC02-05CH11231), Donald A. Roux Family Fund at Jackson Laboratory, Marsico Family at CU Anschutz.


Inhibiting 4EBP1 in Glioblastoma.
Glioblastoma is the most common and aggressive adult brain cancer. Tumors show frequent dysregulation of the PI3K-mTOR pathway. Although a number of small molecules target the PI3K-AKT-mTOR axis, their preclinical and clinical efficacy has been limited. Reasons for treatment failure include poor penetration of agents into the brain and observations that blockade of PI3K or AKT minimally affects downstream mTOR activity in glioma. Clinical trials using allosteric mTOR inhibitors (rapamycin and rapalogs) to treat patients with glioblastoma have also been unsuccessful or uncertain, in part, because rapamycin inefficiently blocks the mTORC1 target 4EBP1 and feeds back to activate PI3K-AKT signaling. Inhibitors of the mTOR kinase (TORKi) such as TAK-228/MLN0128 interact orthosterically with the ATP- and substrate-binding pocket of mTOR kinase, efficiently block 4EBP1 in vitro, and are currently being investigated in the clinical trials. Preclinical studies suggest that TORKi have poor residence times of mTOR kinase, and our data suggest that this poor pharmacology translates into disappointing efficacy in glioblastoma xenografts. RapaLink-1, a TORKi linked to rapamycin, represents a drug with improved pharmacology against 4EBP1. In this review, we clarify the importance of 4EBP1 as a biomarker for the efficacy of PI3K-AKT-mTOR inhibitors in glioblastoma. We also review mechanistic data by which RapaLink-1 blocks p-4EBP1 and discuss future clinical strategies for 4EBP1 inhibition in glioblastoma. Clin Cancer Res; 24(1); 14-21. ©2017 AACR.


Linkages among reproductive health, maternal health, and perinatal outcomes.
Some interventions in women before and during pregnancy may reduce perinatal and neonatal deaths, and recent research has established linkages of reproductive health with maternal, perinatal, and early neonatal health outcomes. In this review, we attempted to analyze the impact of biological, clinical, and epidemiologic aspects of reproductive and maternal health interventions on perinatal and neonatal outcomes through an elucidation of a biological framework for linking reproductive, maternal and newborn health (RHMNH); care strategies and interventions for improved perinatal and neonatal health outcomes; public health implications of these linkages and implementation strategies; and evidence gaps for scaling up such strategies. Approximately 1000 studies (up to June 15, 2010) were reviewed that have addressed an impact of reproductive and maternal health interventions on perinatal and neonatal outcomes. These include systematic reviews, meta-analyses, and stand-alone experimental and observational studies. Evidences were also drawn from recent work undertaken by the Child Health Epidemiology Reference Group (CHERG), the interconnections between maternal and newborn health reviews identified by the Global Alliance for Prevention of Prematurity and Stillbirth (GAPPS), as well as relevant work by the Partnership for Maternal, Newborn and Child Health. Our review amply demonstrates that opportunities for assessing outcomes for both mothers and newborns have been poorly realized and documented. Most of the interventions reviewed will require more greater-quality evidence before solid programmatic recommendations can be made. However, on the basis of our review, birth spacing, prevention of indoor air pollution, prevention of intimate partner violence before and during pregnancy, antenatal care during pregnancy, Doppler ultrasound monitoring during pregnancy, insecticide-treated mosquito nets, birth and newborn care preparedness via community-based intervention packages, emergency obstetrical care, elective induction for postterm delivery, Cesarean delivery for breech presentation, and prophylactic corticosteroids in preterm labor reduce perinatal mortality; and early initiation of breastfeeding and birth and newborn care preparedness through community-based intervention packages reduce neonatal mortality. This review demonstrates that RHMNH are inextricably linked, and that, therefore, health policies and programs should link them together. Such potential integration of strategies would not only help improve outcomes for millions of mothers and newborns but would also save scant resources. This would also allow for greater efficiency in training, monitoring, and supervision of health care workers and would also help families and communities to access and use services easily.


Constancy of bond strength in 5 single-bottle dentin bonding systems.
Historically, wide variations in the shear bond strength of resin composite bonded to dentin have been reported. The purpose of this study was to compare 5 commercially available single-bottle dentin bonding systems while controlling several sources of variation in shear bond strengths. Extracted molars were stored for 2 weeks in 0.5% Chloramine T. The teeth were mounted, the occlusal enamel was removed to expose middle dentin, and the exposed dentin was etched and treated according to 1 of 6 protocols. Finally, a cylinder of resin-based composite was bonded to the dentin. After 24 hours, specimens were fractured under shear force, and the results were recorded in megapascals. The type of product used was significantly associated with the mean shear bond strength observed. All products exhibited some degree of variation from specimen to specimen. One product, PQ1, exhibited less variation than the other 4 products. PQ1 was found to have a significantly higher mean shear bond strength than the other 4 products tested. There was no significant difference between specimens bonded to dry dentin and specimens bonded to wet dentin when using PQ1.


Effects of dry needling of active trigger points in the scalene muscles in individuals with mechanical neck pain: a randomized clinical trial.
The aim of this study was to compare the effects of dry needling (DN) versus pressure release over scalene muscle trigger points (TrPs) on pain, related disability, and inspiratory vital capacity in individuals with neck pain. In this randomized, single-blind trial, 30 patients with mechanical neck pain and active TrPs in the scalene musculature were randomly allocated to trigger point dry needling (TrP-DN; n = 15) or pressure release (n = 15) groups. The DN group received a single session of DN of active TrPs in the anterior scalene muscles, and the pressure release group received a single session of TrP pressure release over the same muscle lasting 30 s. The primary outcome was pain intensity as assessed by a numerical pain rate scale (NPRS, 0-10). Secondary outcomes included disability (neck disability index, NDI) and inspiratory vital capacity. Outcomes were assessed at baseline and 1 day (immediately post), 1 week, and 1 month after the treatment session. Data were expressed as mean score difference (Δ) and standardized mean difference (SMD). Patients receiving DN exhibited a greater decrease in pain intensity than those receiving TrP pressure release at 1 month (Δ 1.2 (95% CI-1.8, -0.6), p = 0.01), but not immediately (1 day) or 1 week after. Patients in the DN group exhibited a greater increase in inspiratory vital capacity at all follow-up time points (Δ 281 mm (95% CI 130, 432) immediately after, Δ 358 mm (95% CI 227, 489) 1 week after, and Δ 310 mm (95% CI 180, 440) 1 month after treatment) than those in the pressure release group (p = 0.006). Between-group effect sizes were large at all follow-up time points (1.1 > SMD > 1.3) in favor of DN. This trial suggests that a single session of DN over active TrPs in the scalene muscles could be effective at reducing pain and increasing inspiratory vital capacity in individuals with mechanical neck pain. Future studies are needed to further confirm these results.


Fluorine-induced polarity increases inhibitory activity of BPTI towards chymotrypsin.
Substituting the P1 position in bovine pancreatic trypsin inhibitor (BPTI) is known to heavily influence its inhibitory activity towards serine proteases. Side-chain fluorinated aliphatic amino acids have been shown to alter numerous properties of peptides and proteins and thus are of interest in the context of BPTI. In our study, we systematically investigated the site-specific incorporation of non-canonical amino acids into BPTI by microwave-assisted solid-phase peptide synthesis (SPPS). Inhibitor activity of the variants was tested towards the serine protease α-chymotrypsin. We observed enhanced inhibition of two fluorinated BPTIs compared to wild type and hydrocarbon variants. To further investigate the complexes, we performed X-ray structure analysis. Our findings underline the power fluorine offers as a tool in protein engineering to beneficially alter the effects on phenomena as protein-protein interactions.


Gender differences in the relative age effect among US olympic development program youth soccer players.
A large body of research has shown that a disproportionate number of elite youth male soccer players competing in age-segmented competition are born early in the selection year. The advantage of being born early in a cohort has been termed the "relative age effect". Although there has been an exponential growth in women's soccer, few studies have examined the relative age effect in female youth soccer. This study compared the relative age effect of 1,344 female and male youth soccer players considered by the US Olympic Development Program (ODP), in 2001, to be the most talented soccer players born in 1984. The birth dates were taken from the women's state and regional ODP, and national team rosters, and were analysed using basic descriptive statistics and chi-square tests. Results revealed only a marginal relative age effect for female ODP regional and national team players and no relative age effect for female ODP state team players. In comparison, a strong relative age effect was found in male state, regional and national team players. The results suggest that there are gender differences in the relative age effect of 17-year-old elite female and male soccer players. The gender differences may be explained by a complex interaction of biological and maturational differences with socialization influences.


Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance).
Optimal adjuvant chemotherapy for early-stage breast cancer balances efficacy and toxicity. We sought to determine whether single-agent paclitaxel (T) was inferior to doxorubicin and cyclophosphamide (AC), when each was administered for four or six cycles of therapy, and whether it offered less toxicity. Patients with operable breast cancer with 0 to 3 positive nodes were enrolled onto the study to address the noninferiority of single-agent T to AC, defined as the one-sided 95% upper-bound CI (UCB) of hazard ratio (HR) of T versus AC less than 1.30 for the primary end point of relapse-free survival (RFS). As a 2 × 2 factorial design, duration of therapy was also addressed and was previously reported. With 3,871 patients enrolled onto the trial, a median follow-up period of 6.1 years, and 437 RFS events, we achieved an HR of 1.26 (one sided 95% UCB, 1.48; favoring AC does not allow a conclusion of noninferiority of T with AC; UCB > 1.3). With 266 patient deaths, the HR for overall survival (OS) was 1.27 favoring AC (UCB, 1.56). The estimated absolute advantage of AC at 5 years is 3% for RFS (91 v 88%) and 1% for OS (95 v 94%). All nine treatment-related deaths were patients receiving AC and are included in the analyses of both RFS and OS. Hematologic toxicity was more common in patients treated with AC, and neuropathy was more common in patients treated with T. This trial did not show noninferiority of T to AC, a conclusion that is unlikely to change with additional events and follow-up. T was less toxic than AC.


Colour pattern variation forms local background matching camouflage in a leaf-mimicking toad.
Optimal camouflage can, in principle, be relatively easily achieved in simple, homogeneous, environments where backgrounds always have the same colour, brightness and patterning. Natural environments are, however, rarely homogenous, and species often find themselves viewed against varied backgrounds where the task of concealment is more challenging. One result of variable backgrounds is the evolution of intraspecific phenotypic variation which may either be generalized, with multiple similarly cryptic patterns, or specialized, with each discrete colour form maximizing concealment against a single component of the background. We investigated the role of phenotypic variation in a highly variable population of the Neotropical toad Rhinella margaritifera using visual modelling and a computer-based detection task. We found that phenotypic variation was not divided into discrete colour morphs, and all toads were well camouflaged against the forest floor. However, although the whole population may appear to consist of random samples from the background, the toads were a particularly close match to the leaf litter, suggesting that they masquerade as dead leaves, which are themselves variable. Furthermore, rather than each colour form being equally effective against a single background, each toad was specialized towards its own particular local surroundings, as suggested by a specialist strategy. Taken together, these data highlight the importance of background matching to a nominally masquerading species, as well as how habitat heterogeneity at multiple spatial scales may affect the evolution of camouflage and phenotypic variation.


Methodical evaluation and improvement of matrix compatible PDMS-overcoated coating for direct immersion solid phase microextraction gas chromatography (DI-SPME-GC)-based applications.
The main quest for the implementation of direct SPME to complex matrices has been the development of matrix compatible coatings that provide sufficient sensitivity towards the target analytes. In this context, we present here a thorough evaluation of PDMS-overcoated fibers suitable for simultaneous extraction of different polarities analytes, while maintaining adequate matrix compatibility. For this, eleven analytes were selected, from various application classes (pesticides, industrial chemicals and pharmaceuticals) and with a wide range of log P values (ranging from 1.43 to 6). The model matrix chosen was commercial Concord grape juice, which is rich in pigments such as anthocyanins, and contains approximately 20% of sugar (w/w). Two types of PDMS, as well as other intrinsic factors associated with the PDMS-overcoated fiber fabrication are studied. The evaluation showed that the PDMS-overcoated fibers considerably slowed down the coating fouling process during direct immersion in complex matrices of high sugar content. Longevity differences could be seen between the two types of PDMS tested, with a proprietary Sylgard(®) giving superior performance because of lesser amount of reactive groups and enhanced hydrophobicity. Conversely, the thickness of the outer layer did not seem to have a significant effect on the fiber lifetime. We also demonstrate that the uniformity of the overcoated PDMS layer is paramount to the achievement of reliable data and extended fiber lifetime. Employing the optimum overcoated fiber, limits of detection (LOD) in the range of 0.2-1.3 ng/g could be achieved. Additional improvement is attainable by introducing washing of the coatings after desorption, so that any carbon build-up (fouling) left on the coating surface after thermal desorption can be removed.


Transnational, social, and neighborhood ties and smoking among Latino immigrants: does gender matter?
We examined whether transnational ties, social ties, and neighborhood ties were independently associated with current smoking status among Latino immigrants. We also tested interactions to determine whether these associations were moderated by gender. We conducted a series of weighted logistic regression analyses (i.e., economic remittances, number of return visits, friend support, family support, and neighborhood cohesion) using the Latino immigrant subsample (n = 1629) of the National Latino and Asian American Study in 2002 and 2003. The number of past-year return visits to the country-of-origin was positively associated with current smoker status. Gender moderated the association between economic remittances, friend support, and smoking. Remittance behavior had a protective association with smoking, and this association was particularly pronounced for Latino immigrant women. Friendship support lowered the odds of smoking among men, but not women. Our results underscore the growing importance of transnational networks for understanding Latino immigrant health and the gendered patterns of the associations between social ties, transnational ties, and health risk behaviors.


Evidence for modulation of smooth muscle force by the p38 MAP kinase/HSP27 pathway.
Mitogen-activated protein (MAP) kinases signal to proteins that could modify smooth muscle contraction. Caldesmon is a substrate for extracellular signal-related kinases (ERK) and p38 MAP kinases in vitro and has been suggested to modulate actin-myosin interaction and contraction. Heat shock protein 27 (HSP27) is downstream of p38 MAP kinases presumably participating in the sustained phase of muscle contraction. We tested the role of caldesmon and HSP27 phosphorylation in the contractile response of vascular smooth muscle by using inhibitors of both MAP kinase pathways. In intact smooth muscle, PD-098059 abolished endothelin-1 (ET-1)-stimulated phosphorylation of ERK MAP kinases and caldesmon, but p38 MAP kinase activation and contractile response remained unaffected. SB-203580 reduced muscle contraction and inhibited p38 MAP kinase and HSP27 phosphorylation but had no effect on ERK MAP kinase and caldesmon phosphorylation. In permeabilized muscle fibers, SB-203580 and a polyclonal anti-HSP27 antibody attenuated ET-1-dependent contraction, whereas PD-098059 had no effect. These results suggest that ERK MAP kinases phosphorylate caldesmon in vivo but that activation of this pathway is unnecessary for force development. The generation of maximal force may be modulated by the p38 MAP kinase/HSP27 pathway.


Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases.
TGF-betas are potent inhibitors of epithelial cell proliferation. However, in established carcinomas, autocrine/paracrine TGF-beta interactions can enhance tumor cell viability and progression. Thus, we studied the effect of a soluble Fc:TGF-beta type II receptor fusion protein (Fc:TbetaRII) on transgenic and transplantable models of breast cancer metastases. Systemic administration of Fc:TbetaRII did not alter primary mammary tumor latency in MMTV-Polyomavirus middle T antigen transgenic mice. However, Fc:TbetaRII increased apoptosis in primary tumors, while reducing tumor cell motility, intravasation, and lung metastases. These effects correlated with inhibition of Akt activity and FKHRL1 phosphorylation. Fc:TbetaRII also inhibited metastases from transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c mice. Tumor microvessel density in a mouse dorsal skin window chamber was unaffected by Fc:TbetaRII. Therefore, blockade of TGF-beta signaling may reduce tumor cell viability and migratory potential and represents a testable therapeutic approach against metastatic carcinomas.


Subspecialty surveillance of long-term course of small and moderate muscular ventricular septal defect: heterogenous practices, low yield.
No expert consensus guides practice for intensity of ongoing pediatric cardiology surveillance of hemodynamically insignificant small and moderate muscular ventricular septal defect (mVSD). Therefore, despite the well-established benign natural history of mVSD, there is potential for widely divergent follow up practices. The purpose of this investigation was to evaluate (1) variations in follow up of mVSD within an academic children's hospital based pediatric cardiology practice, and (2) the frequency of active medical or surgical management resulting from follow up of mVSD. We retrospectively reviewed records of 600 patients with isolated mVSD echocardiographically diagnosed between 2006 and 2012. Large mVSD were excluded (n = 4). Patient age, gender, echocardiographic findings, provider, recommendations for follow up, and medical and surgical management were tabulated at initial and follow up visits. Independent associations with follow up recommendations were sought using multivariate analysis. Initial echocardiography showed small single mVSD in 509 (85%), multiple small mVSD in 60 (10%), and small-to-moderate or moderate single mVSD in 31 (5%). The mean age at diagnosis was 15.9 months (0-18.5 years) and 25.7 months (0-18.5 years) at last follow up. There was slight female predominance (56.3%). Fourteen pediatric cardiology providers recommended 316 follow up visits, 259 of which were actually accomplished. There were 37 other unplanned follow up visits. No medical or surgical management changes were associated with any of the follow up visits. The proportion of patients for whom follow up was advised varied among providers from 11 to 100%. Independent associations with recommendation for follow up were limited to the identity and clinical volume of the provider, age of the patient, and the presence of multiple, small-to-moderate, or moderate mVSD. In this large series of moderate or smaller mVSD, pediatric cardiology follow up was commonly recommended but resulted in no active medical or surgical management. Major provider based inconsistency in intensity of follow up of mVSD was identified, but is difficult to justify.


[Thermostable alkaline phosphatase from Thermus sp. FD3041: cloning of the gene and expression in Escherichia coli].
A genomic library of Thermus sp. FD3041 which produces thermostable alkaline phosphatase (FD-TAP) was constructed with the vector pUC118 and the host E. coli TG1. 3-10kb inserted fragments of foreign DNA were identified in 90 percent of the 12,000 clones thus obtained. Five positive clones were detected after screening the plated library by the method of colony coloration for TAP in situ. Preliminary analysis of the enzyme expressed from one recombinant plasmid pTAP362 showed that the properties of the recombinant enzyme, such as the thermal stability and optimal temperature of reaction, were identical to those of the native enzyme. The gene of FD-TAP was located on the 2.0kb BamHI-HindIII fragment of the pTAP362, determined by its physical map and the change of enzyme activity in different partially deleted plasmids. Results of thermostability experiment in PCR thermal cycle showed that the FD-TAP would be suitable for labelling of primers and detection of PCR amplified products.


Mechanisms that determine the internal environment of the developing brain: a transcriptomic, functional and ultrastructural approach.
We provide comprehensive identification of embryonic (E15) and adult rat lateral ventricular choroid plexus transcriptome, with focus on junction-associated proteins, ionic influx transporters and channels. Additionally, these data are related to new structural and previously published permeability studies. Results reveal that most genes associated with intercellular junctions are expressed at similar levels at both ages. In total, 32 molecules known to be associated with brain barrier interfaces were identified. Nine claudins showed unaltered expression, while two claudins (6 and 8) were expressed at higher levels in the embryo. Expression levels for most cytoplasmic/regulatory adaptors (10 of 12) were similar at the two ages. A few junctional genes displayed lower expression in embryos, including 5 claudins, occludin and one junctional adhesion molecule. Three gap junction genes were enriched in the embryo. The functional effectiveness of these junctions was assessed using blood-delivered water-soluble tracers at both the light and electron microscopic level: embryo and adult junctions halted movement of both 286Da and 3kDa molecules into the cerebrospinal fluid (CSF). The molecular identities of many ion channel and transporter genes previously reported as important for CSF formation and secretion in the adult were demonstrated in the embryonic choroid plexus (and validated with immunohistochemistry of protein products), but with some major age-related differences in expression. In addition, a large number of previously unidentified ion channel and transporter genes were identified for the first time in plexus epithelium. These results, in addition to data obtained from electron microscopical and physiological permeability experiments in immature brains, indicate that exchange between blood and CSF is mainly transcellular, as well-formed tight junctions restrict movement of small water-soluble molecules from early in development. These data strongly indicate the brain develops within a well-protected internal environment and the exchange between the blood, brain and CSF is transcellular and not through incomplete barriers.


Trust, the asymmetry principle, and the role of prior beliefs.
Within the risk literature there is an ongoing debate on whether trust is vulnerable or enduring. Previous research on nuclear energy by Slovic in 1993 has shown that negative events have much greater impact on self-reported trust than do positive events. Slovic attributes this to the asymmetry principle: specifically, that trust is much easier to destroy than to create. In a questionnaire survey concerning genetically modified (GM) food in Britain (n= 396) we similarly find that negative events have a greater impact on trust than positive events. Because public opinion in Britain is skewed in the direction of opposition toward GM food, the pattern of results could either be caused by the fact that negative information is more informative than positive information (a negativity bias) or reflect the influence of people's prior attitudes toward the issue (a confirmatory bias). The results were largely in line with the confirmatory bias hypothesis: participants with clear positive or negative beliefs interpreted events in line with their existing attitude position. However, for participants with intermediate attitudes, negative items still had greater impact than the positive. This latter finding suggests that, congruent with the negativity bias hypothesis, negative information may still be more informative than positive information for undecided people. The study also identified the labeling of GM products, consulting the public, making biotechnology companies liable for any damage, and making a test available to detect GM produce as being particularly important preconditions for maintaining trust in the regulation of agricultural biotechnology.


Treating IgA nephropathy: quid novi?
IgA nephropathy is a common autoimmune renal disease resulting in kidney failure for patients with significant proteinuria. The therapeutic options are limited including non-specific treatment to reduce proteinuria accomplished by renin-angiotensin blockade. Strategies to control intrarenal inflammation include the administration of fish oil and for severe disease the use of immunosuppressive agents such as cyclophosphamide, glucocorticosteroids, and mycophenolate mofetil. In light of the limited option, there is an unmet need for novel therapeutic intervention in patients with progressive disease. Herein, we review the evidence for existing treatment choices and explore new immunopharmacologic agents being investigated for IgA nephropathy.


Induction of activator protein 1 (AP-1) in macrophages by human immunodeficiency virus type-1 NEF is a cell-type-specific response that requires both hck and MAPK signaling events.
Human immunodeficiency virus type 1 (HIV-1) Nef is important for viral infectivity and pathogenicity. HIV-1 infection is associated with inappropriate activation and defects in the function of monocytes/macrophages. We have studied the effects of HIV-1 Nef in the murine (RAW264.7) and human (THP-1) monocyte-macrophage cell lines. Investigation of the activator protein-1 (AP-1) transcription factor showed that Nef expression induced both its DNA binding and transcriptional activities. Increased AP-1 DNA binding activity in RAW264.7 cells was associated with raised levels of c-Fos expression and induction of mRNA for the AP-1 responsive tissue inhibitor of metalloproteinases-1 (TIMP-1) gene. Mutagenesis and kinase inhibition studies were employed to determine signaling pathways used by Nef to induce AP-1. Data from these studies indicated that induction of AP-1 by Nef is likely to be mediated through the MAPK (ERK1 and 2) signaling pathway and requires the proline-rich PxxP motif of Nef, suggesting the involvement of upstream protein kinases belonging to the Src family. Effects of Nef on AP-1 induction were cell lineage-specific, being stimulatory in macrophages, inhibitory in T cells and without effect in HeLa cells. These latter two observations led us to test the possibility that cell-specific interactions of Nef with Src family proteins may modulate AP-1 activity. To this end we demonstrated that a dominant-negative Hck mutant caused inhibition of Nef-mediated AP-1 DNA binding activity in RAW cells. In conclusion, induction of AP-1 by Nef is a specific feature of human and murine macrophage cell lines that requires signal transduction events involving Hck and MAPKs.


Shed urinary ALCAM is an independent prognostic biomarker of three-year overall survival after cystectomy in patients with bladder cancer.
Proteins involved in tumor cell migration can potentially serve as markers of invasive disease. Activated Leukocyte Cell Adhesion Molecule (ALCAM) promotes adhesion, while shedding of its extracellular domain is associated with migration. We hypothesized that shed ALCAM in biofluids could be predictive of progressive disease. ALCAM expression in tumor (n = 198) and shedding in biofluids (n = 120) were measured in two separate VUMC bladder cancer cystectomy cohorts by immunofluorescence and enzyme-linked immunosorbent assay, respectively. The primary outcome measure was accuracy of predicting 3-year overall survival (OS) with shed ALCAM compared to standard clinical indicators alone, assessed by multivariable Cox regression and concordance-indices. Validation was performed by internal bootstrap, a cohort from a second institution (n = 64), and treatment of missing data with multiple-imputation. While ALCAM mRNA expression was unchanged, histological detection of ALCAM decreased with increasing stage (P = 0.004). Importantly, urine ALCAM was elevated 17.0-fold (P < 0.0001) above non-cancer controls, correlated positively with tumor stage (P = 0.018), was an independent predictor of OS after adjusting for age, tumor stage, lymph-node status, and hematuria (HR, 1.46; 95% CI, 1.03-2.06; P = 0.002), and improved prediction of OS by 3.3% (concordance-index, 78.5% vs. 75.2%). Urine ALCAM remained an independent predictor of OS after accounting for treatment with Bacillus Calmette-Guerin, carcinoma in situ, lymph-node dissection, lymphovascular invasion, urine creatinine, and adjuvant chemotherapy (HR, 1.10; 95% CI, 1.02-1.19; P = 0.011). In conclusion, shed ALCAM may be a novel prognostic biomarker in bladder cancer, although prospective validation studies are warranted. These findings demonstrate that markers reporting on cell motility can act as prognostic indicators.


'This is our liver patient…': use of narratives during resident and nurse handoff conversations.
Handoffs are often framed as the co-construction of a shared understanding relying on narrative storytelling. We investigated how narratives are constructed and used during resident and nurse handoff conversations. We audio-recorded resident (n=149) and nurse (n=126) handoffs in an inpatient medicine unit. Qualitative analysis using grounded theory was conducted to identify and characterise the structure of resident and nursing handoff narratives. Handoff conversations among both residents and nurses used three types of narratives: narratives on creating clinical imagery, narratives on coordinating care continuity and narratives on integrating contextual aspects of care. Clinical imagery narratives were common during patient introductions: residents used a top-down approach relying on overarching patient clinical situations (eg, 'a liver patient'), whereas nurses used a bottom-up approach using patient-specific identifying information. Narratives on the coordination of care continuity for residents focused on managing internal and external coordination activities, whereas nurse narratives focused on internal coordination, emphasising their role as an interface between patients and their physicians. Both resident and nurse narratives on the contextual aspects of care had considerable focus on highlighting 'heads up' anticipatory information and personal patient information; such information was often not present in patient charts, but was important for ensuring effective care management. The presence of narrative structures highlights the need for new perspectives for the design of handoff tools that allow for both informational and cognitive support and shared awareness among conversational partners during handoff conversations. We discuss the implications of the use of narratives for patient safety and describe specific design considerations for supporting narrative interactions during handoffs.


Structured neural networks for pattern recognition.
This paper proposes a novel approach for the design of structures of neural networks for pattern recognition. The basic idea lies in subdividing the whole classification problem in smaller and simpler problems at different levels, each managed by appropriate components of a complex neural architecture. Three neural structures are presented and applied in a surveillance system aimed at monitoring a railway waiting room classifying potential dangerous situations. Each architecture is composed by nodes, which are actual multilayer perceptrons trained to discriminate between subsets of classes until a complete separation among the classes is achieved. This approach showed better performances with respect to a classical statistical classification procedures and to a single neural network.


Human articular chondrocytes express ChemR23 and chemerin; ChemR23 promotes inflammatory signalling upon binding the ligand chemerin(21-157).
Chemerin is a chemotactic peptide which directs leukocytes expressing the chemokine-like receptor ChemR23 towards sites of inflammation. ChemR23 is a G protein-coupled receptor which binds several different ligands, and it is also expressed by other cell types such as adipocytes. In addition to chemotaxis, recent reports suggest that ChemR23 is capable of mediating either inflammatory or anti-inflammatory effects, depending on the type of ligand it binds. In the present study, we aimed to clarify whether human chondrocytes express ChemR23 and chemerin, and whether chemerin/ChemR23 signalling could affect secretion of inflammatory mediators. Tissue sections were taken from human knee joints and labelled with antibodies towards chemerin and ChemR23. Chondrocytes from cartilage tissue were isolated, cultured and assessed for chemerin and ChemR23 expression by PCR and immunolabelling. Receptor activation and intracellular signalling were studied by assessment of phosphorylated mitogen activated protein kinases (MAPKs) and phosphorylated Akt after stimulating cells with recombinant chemerin(21-157). Biological effects of chemerin(21-157) were investigated by measuring secretion of pro-inflammatory cytokines and metalloproteases in cell supernatants. Both serially cultured human articular chondrocytes and resident cells in native cartilage expressed chemerin and ChemR23. Stimulating cells with chemerin(21-157) resulted in phosphorylation of p44/p42 MAPKs (ERK 1/2) and Akt (Ser 473). Also, significantly enhanced levels of the pro-inflammatory cytokines interleukin-6 (IL-6), interleukin-8 (IL-8), tumour necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and the matrix metalloproteases MMP-1, MMP-2, MMP-3, MMP-8 and MMP-13 were detected. These results demonstrate that human chondrocytes express both the receptor ChemR23 and the ligand chemerin. Chemerin(21-157) stimulation engaged signal-transduction pathways that further promoted inflammatory signalling in chondrocytes, as judged by an enhanced secretion of cytokines and metalloproteases. Taken together, the previously reported chemotaxis and the present findings suggest that the receptor and its ligand may play pivotal roles in joint inflammation.


Binge drinking and associated health risk behaviors among high school students.
Underage drinking contributes to the 3 leading causes of death (unintentional injury, homicide, and suicide) among persons aged 12 to 20 years. Most adverse health effects from underage drinking stem from acute intoxication resulting from binge drinking. Although binge drinking, typically defined as consuming > or = 5 drinks on an occasion, is a common pattern of alcohol consumption among youth, few population-based studies have focused specifically on the characteristics of underage binge drinkers and their associated health risk behaviors. We analyzed data on current drinking, binge drinking, and other health risk behaviors from the 2003 National Youth Risk Behavior Survey. Prevalence estimates and 95% confidence intervals were calculated by using SAS and SUDAAN statistical software. Logistic regression was used to examine the associations between different patterns of alcohol consumption and health risk behaviors. Overall, 44.9% of high school students reported drinking alcohol during the past 30 days (28.8% binge drank and 16.1% drank alcohol but did not binge drink). Although girls reported more current drinking with no binge drinking, binge-drinking rates were similar among boys and girls. Binge-drinking rates increased with age and school grade. Students who binge drank were more likely than both nondrinkers and current drinkers who did not binge to report poor school performance and involvement in other health risk behaviors such as riding with a driver who had been drinking, being currently sexually active, smoking cigarettes or cigars, being a victim of dating violence, attempting suicide, and using illicit drugs. A strong dose-response relationship was found between the frequency of binge drinking and the prevalence of other health risk behaviors. Binge drinking is the most common pattern of alcohol consumption among high school youth who drink alcohol and is strongly associated with a wide range of other health risk behaviors. Effective intervention strategies (eg, enforcement of the minimum legal drinking age, screening and brief intervention, and increasing alcohol taxes) should be implemented to prevent underage alcohol consumption and adverse health and social consequences resulting from this behavior.


Partitioning of soil phosphorus regulates competition between Vaccinium vitis-idaea and Deschampsia cespitosa.
It has been hypothesized that the wide range of forms and complexities of phosphorus (P) in soil may result in resource partitioning that contributes to the maintenance of plant species diversity. Here, we test whether the graminoid, Deschampsia cespitosa, and the ericaceous shrub, Vaccinium vitis-idaea, which often coexist, display preferences in utilization of P forms, and differ in their production of extracellular P-degrading enzymes. We provided plants with no additional P, or P forms with decreasing lability, namely sodium phosphate (SP), D-glucose 6 phosphate (DG6P), sodium phytate (PASS), and a combination of SP, DG6P, and PASS. We also tested if preferences for P forms affected the competitive outcomes between the two species compared between conspecifics, as indicated by shoot biomass and acquisition of nitrogen (N) and P. Both D. cespitosa and V. vitis-idaea produced the greatest biomass when supplied with a mix of all three forms of P. Of the three forms of P tested alone, shoot biomass produced by both species was least when supplied with SP. D. cespitosa performed better when grown with PASS or a mix of all P forms compared with the performance of V. vitis-idaea on these substrates. This was reflected by substantially greater phytase activity on the surface of its roots compared with V. vitis-idaea. In contrast, V. vitis-idaea produced more phosphomonoesterase to hydrolyze the simple organic P form, DG6P. Although N was kept constant in the treatments, the ability of plants to acquire it was dependent on species identity, competition, and P supply. These findings provide direct evidence for preferences toward specific forms of P and indicate a key role played by organic forms of P. The results support the idea that partitioning for soil P is one factor regulating plant competition, and ultimately, community composition. Our data also highlight the importance of the interplay between P supply and N acquisition.


Fast and furious: Early differences in growth rate drive short-term plant dominance and exclusion under eutrophication.
The reduction of plant diversity following eutrophication threatens many ecosystems worldwide. Yet, the mechanisms by which species are lost following nutrient enrichment are still not completely understood, nor are the details of when such mechanisms act during the growing season, which hampers understanding and the development of mitigation strategies.Using a common garden competition experiment, we found that early-season differences in growth rates among five perennial grass species measured in monoculture predicted short-term competitive dominance in pairwise combinations and that the proportion of variance explained was particularly greater under a fertilization treatment.We also examined the role of early-season growth rate in determining the outcome of competition along an experimental nutrient gradient in an alpine meadow. Early differences in growth rate between species predicted short-term competitive dominance under both ambient and fertilized conditions and competitive exclusion under fertilized conditions.The results of these two studies suggest that plant species growing faster during the early stage of the growing season gain a competitive advantage over species that initially grow more slowly, and that this advantage is magnified under fertilization. This finding is consistent with the theory of asymmetric competition for light in which fast-growing species can intercept incident light and hence outcompete and exclude slower-growing (and hence shorter) species. We predict that the current chronic nutrient inputs into many terrestrial ecosystems worldwide will reduce plant diversity and maintain a low biodiversity state by continuously favoring fast-growing species. Biodiversity management strategies should focus on controlling nutrient inputs and reducing the growth of fast-growing species early in the season.


Older lesbian and gay men's perceptions on lesbian and gay youth in Australia.
Older lesbian and gay people are increasingly open about their sexuality but have also experienced a lifetime of discrimination. These groups have experienced a long history of changes to lesbian and gay rights, and many were also at the forefront of activist movements during the latter half of the 20th century. A deeper knowledge is needed of the life experiences of these groups, including how they view their lives in relation to younger lesbian and gay people. This would assist agencies working with older lesbian and gay people, such as health and support services, to provide more informed engagement, support, understanding, and culturally safe services. Drawing on 33 qualitative interviews with older (60+ years) lesbian and gay people, we explored their experiences during their younger years and their perspectives on how these experiences compare with those of younger lesbian and gay people today. Our findings note that older lesbian and gay people feel life is, in some ways, easier, and in others, still challenging for young lesbian and gay people, and they articulate a need for mutual respect across age groups.


Embryonic expression of priapulid Wnt genes.
Posterior elongation of the developing embryo is a common feature of animal development. One group of genes that is involved in posterior elongation is represented by the Wnt genes, secreted glycoprotein ligands that signal to specific receptors on neighbouring cells and thereby establish cell-to-cell communication. In segmented animals such as annelids and arthropods, Wnt signalling is also likely involved in segment border formation and regionalisation of the segments. Priapulids represent unsegmented worms that are distantly related to arthropods. Despite their interesting phylogenetic position and their importance for the understanding of ecdysozoan evolution, priapulids still represent a highly underinvestigated group of animals. Here, we study the embryonic expression patterns of the complete sets of Wnt genes in the priapulids Priapulus caudatus and Halicryptus spinulosus. We find that both priapulids possess a complete set of 12 Wnt genes. At least in Priapulus, most of these genes are expressed in and around the posterior-located blastopore and thus likely play a role in posterior elongation. Together with previous work on the expression of other genetic factors such as caudal and even-skipped, this suggests that posterior elongation in priapulids is under control of the same (or very similar) conserved gene regulatory network as in arthropods.


[The territorial basis of the Brazilian National Health System: mapping hospital networks].
This article presents two types of networks organized according to patient caseload in health services, concerning both primary hospital care (most frequent hospital procedures) and tertiary care (high-cost procedures). Data on inpatient care in Brazil in 2000 obtained from the Hospital Information System of the Unified National Health System were aggregated by place of residence and hospital location at the municipal level. Both the network structure and the node (municipality) hierarchy were established using the dominant flow approach. In addition, a typology of flows was applied to indicate the degree of connection across the networks. Primary hospital care networks reach most of the country, and few municipalities are not connected to the network. Relatively few cities provide higher-level services, and almost half of the municipalities are unconnected. The Ministry of Health aims to provide access to frequently used health services near the users' place of residence, and this goal appears to be feasible in the short run. On the other hand, much remains to be done to ensure widespread access to tertiary care.


Drosophila Src regulates anisotropic apical surface growth to control epithelial tube size.
Networks of epithelial and endothelial tubes are essential for the function of organs such as the lung, kidney and vascular system. The sizes and shapes of these tubes are highly regulated to match their individual functions. Defects in tube size can cause debilitating diseases such as polycystic kidney disease and ischaemia. It is therefore critical to understand how tube dimensions are regulated. Here we identify the tyrosine kinase Src as an instructive regulator of epithelial-tube length in the Drosophila tracheal system. Loss-of-function Src42 mutations shorten tracheal tubes, whereas Src42 overexpression elongates them. Surprisingly, Src42 acts distinctly from known tube-size pathways and regulates both the amount of apical surface growth and, with the conserved formin dDaam, the direction of growth. Quantitative three-dimensional image analysis reveals that Src42- and dDaam-mutant tracheal cells expand more in the circumferential than the axial dimension, resulting in tubes that are shorter in length-but larger in diameter-than wild-type tubes. Thus, Src42 and dDaam control tube dimensions by regulating the direction of anisotropic growth, a mechanism that has not previously been described.


Mechanisms of pressure-diuresis and pressure-natriuresis in Dahl salt-resistant and Dahl salt-sensitive rats.
Data on blood flow regulation, renal filtration, and urine output in salt-sensitive Dahl S rats fed on high-salt (hypertensive) and low-salt (prehypertensive) diets and salt-resistant Dahl R rats fed on high-salt diets were analyzed using a mathematical model of renal blood flow regulation, glomerular filtration, and solute transport in a nephron. The mechanism of pressure-diuresis and pressure-natriuresis that emerges from simulation of the integrated systems is that relatively small increases in glomerular filtration that follow from increases in renal arterial pressure cause relatively large increases in urine and sodium output. Furthermore, analysis reveals the minimal differences between the experimental cases necessary to explain the observed data. It is determined that differences in renal afferent and efferent arterial resistances are able to explain all of the qualitative differences in observed flows, filtration rates, and glomerular pressure as well as the differences in the pressure-natriuresis and pressure-diuresis relationships in the three groups. The model is able to satisfactorily explain data from all three groups without varying parameters associated with glomerular filtration or solute transport in the nephron component of the model. Thus the differences between the experimental groups are explained solely in terms of difference in blood flow regulation. This finding is consistent with the hypothesis that, if a shift in the pressure-natriuresis relationship is the primary cause of elevated arterial pressure in the Dahl S rat, then alternation in how renal afferent and efferent arterial resistances are regulated represents the primary cause of chronic hypertension in the Dahl S rat.


Comprehensive screening of octopus amphiphiles as DNA activators in lipid bilayers: implications on transport, sensing and cellular uptake.
Dynamic octopus amphiphiles contain one charged "head," here a guanidinium cation, together several hydrophobic "tails" (or "tentacles") that can be attached and exchanged in situ by reversible hydrazone formation. Quite surprisingly, their ability to activate DNA as transporters in lipid bilayer membranes was found to increase with the number of tails (up to four) as well as with their length (up to eight carbons). Both encouraged and puzzled by these results, we decided that a comprehensive screening of octopus amphiphiles with regard to number (from one to six) and length (from three to eighteen carbons) of their tails would be appropriate at this point. For this purpose, we here report the synthesis of cationic hexahydrazide peptide dendrons together with that of aldehydes with long, saturated, unsaturated and branched hydrophobic tails. Comprehensive screening of the completed collection of tails and heads reveals that the ability of octopus amphiphiles to activate DNA transporters shifts with increasing number of tails to decreasing length of the tails. Moreover, cis-alkenyl and branched alkyl tails are more active than their linear analogs, branched aromatic tails are best. These overall very meaningful trends for octopus amphiphiles will be of importance for sensing applications and fragrant cellular uptake.


The IpaC carboxyterminal effector domain mediates Src-dependent actin polymerization during Shigella invasion of epithelial cells.
Shigella, the causative agent of bacillary dysentery, invades epithelial cells by locally reorganizing the actin cytoskeleton. Shigella invasion requires actin polymerization dependent on the Src tyrosine kinase and a functional bacterial type III secretion (T3S) apparatus. Using dynamic as well as immunofluorescence microscopy, we show that the T3S translocon component IpaC allows the recruitment of the Src kinase required for actin polymerization at bacterial entry sites during the initial stages of Shigella entry. Src recruitment occurred at bacterial-cell contact sites independent of actin polymerization at the onset of the invasive process and was still observed in Shigella strains mutated for translocated T3S effectors of invasion. A Shigella strain with a polar mutation that expressed low levels of the translocator components IpaB and IpaC was fully proficient for Src recruitment and bacterial invasion. In contrast, a Shigella strain mutated in the IpaC carboxyterminal effector domain that was proficient for T3S effector translocation did not induce Src recruitment. Consistent with a direct role for IpaC in Src activation, cell incubation with the IpaC last 72 carboxyterminal residues fused to the Iota toxin Ia (IaC) component that translocates into the cell cytosol upon binding to the Ib component led to Src-dependent ruffle formation. Strikingly, IaC also induced actin structures resembling bacterial entry foci that were enriched in activated Src and were inhibited by the Src inhibitor PP2. These results indicate that the IpaC effector domain determines Src-dependent actin polymerization and ruffle formation during bacterial invasion.


Stem cell niche-specific Ebf3 maintains the bone marrow cavity.
Bone marrow is the tissue filling the space between bone surfaces. Hematopoietic stem cells (HSCs) are maintained by special microenvironments known as niches within bone marrow cavities. Mesenchymal cells, termed CXC chemokine ligand 12 (CXCL12)-abundant reticular (CAR) cells or leptin receptor-positive (LepR+) cells, are a major cellular component of HSC niches that gives rise to osteoblasts in bone marrow. However, it remains unclear how osteogenesis is prevented in most CAR/LepR+ cells to maintain HSC niches and marrow cavities. Here, using lineage tracing, we found that the transcription factor early B-cell factor 3 (Ebf3) is preferentially expressed in CAR/LepR+ cells and that Ebf3-expressing cells are self-renewing mesenchymal stem cells in adult marrow. When Ebf3 is deleted in CAR/LepR+ cells, HSC niche function is severely impaired, and bone marrow is osteosclerotic with increased bone in aged mice. In mice lacking Ebf1 and Ebf3, CAR/LepR+ cells exhibiting a normal morphology are abundantly present, but their niche function is markedly impaired with depleted HSCs in infant marrow. Subsequently, the mutants become progressively more osteosclerotic, leading to the complete occlusion of marrow cavities in early adulthood. CAR/LepR+ cells differentiate into bone-producing cells with reduced HSC niche factor expression in the absence of Ebf1/Ebf3 Thus, HSC cellular niches express Ebf3 that is required to create HSC niches, to inhibit their osteoblast differentiation, and to maintain spaces for HSCs.


The Role of Interferon in the Management of BCG Refractory Nonmuscle Invasive Bladder Cancer.
Background. Thirty to forty percent of patients with high grade nonmuscle invasive bladder cancer (NMIBC) fail to respond to intravesical therapy with bacillus Calmette-Guerin (BCG). Interferon-α2B plus BCG has been shown to be effective in a subset of patients with NMIBC BCG refractory disease. Here we present a contemporary series on the effectiveness and safety of intravesical BCG plus interferon-α2B therapy in patients with BCG refractory NMIBC. Methods. From January of 2005 to April of 2014 we retrospectively found 44 patients who underwent induction with combination IFN/BCG for the management of BCG refractory NMIBC. A chart review was performed to assess initial pathological stage/grade, pathological stage/grade at the time of induction, time to IFN/BCG failure, pathological stage/grade at failure, postfailure therapy, and current disease state. Results. Of the 44 patients who met criteria for the analysis. High risk disease was found in 88.6% of patients at induction. The 12-month and 24-month recurrence-free survival were 38.6% and 18.2%, respectively. 25 (56.8%) ultimately had disease recurrence. Radical cystectomy was performed in 16 (36.4%) patients. Conclusion. Combination BCG plus interferon-α2B remains a reasonably safe alternative treatment for select patients with BCG refractory disease prior to proceeding to radical cystectomy.


Bully/victims: a longitudinal, population-based cohort study of their mental health.
It has been suggested that those who both bully and are victims of bullying (bully/victims) are at the highest risk of adverse mental health outcomes. However, unknown is whether most bully/victims were bullies or victims first and whether being a bully/victim is more detrimental to mental health than being a victim. A total of 4101 children were prospectively studied from birth, and structured interviews and questionnaires were used to assess bullying involvement at 10 years (elementary school) and 13 years of age (secondary school). Mental health (anxiety, depression, psychotic experiences) was assessed at 18 years. Most bully/victims at age 13 (n = 233) had already been victims at primary school (pure victims: n = 97, 41.6 % or bully/victims: n = 47, 20.2 %). Very few of the bully/victims at 13 years had been pure bullies previously (n = 7, 3 %). After adjusting for a wide range of confounders, both bully/victims and pure victims, whether stable or not from primary to secondary school, were at increased risk of mental health problems at 18 years of age. In conclusion, children who are bully/victims at secondary school were most likely to have been already bully/victims or victims at primary school. Children who are involved in bullying behaviour as either bully/victims or victims at either primary or secondary school are at increased risk of mental health problems in late adolescence regardless of the stability of victimization. Clinicians should consider any victimization as a risk factor for mental health problems.


A Pilot Study of Whether the Cold-Heat Syndrome Type is Associated with Treatment Response and Immune Status in Patients with Non-Small Cell Lung Cancer.
The cold-heat syndrome type (ZHENG) is one of the essential elements of syndrome differentiation in East Asian Medicine. This pilot study aimed to explore the characteristics of non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs) based on the cold-heat syndrome type. Twenty NSCLC patients treated with ICI monotherapy were included in the study and completed the cold-heat syndrome differentiation questionnaire. Demographic and clinical characteristics of the included patients were obtained through electronic medical records. Additionally, blood samples of 10 patients were analyzed with cytokine level and immune profiling. Patients were divided into two groups of cold type (n = 9) and non-cold type (n = 11), according to the cold symptoms questionnaire's cutoff point. No significant difference between the two groups was observed in clinical response to ICIs (p=0.668). Progression-free survival (PFS) seemed to be longer in patients with non-cold type than cold type (p=0.332). In patients with adenocarcinoma, the non-cold type showed longer PFS than the cold type (p=0.036). Also, there were more patients with PD-L1 negative in the cold type compared to the non-cold type (p=0.050). In immune profiling, the proportion of effector memory CD8 T-cells was higher in patients with cold type than with non-cold type (p=0.015), and the proportion of terminal effector CD8 T-cells was lower in patients with cold type than with non-cold type (p=0.005). This pilot study has shown the potential for differences in prognosis and immune status between patients with cold and non-cold types. Hopefully, it provides essential information and insight into NSCLC patients' characteristics from the perspective of syndrome differentiation. Further large-scale observational studies and intervention studies are required.


Isolation, Synthesis And Structure Determination Of Cannabidiol Derivatives And Their Cytotoxic Activities.
In a continuing effort to explore the structural diversity and pharmacological activities of natural products based scaffolds, herein, we report the isolation, synthesis, and structure determination of cannabidiol and its derivatives along with their cytotoxic activities. Treatment of cannabidiol (1) with acid catalyst POCl3 afforded a new derivative 6 along with six known molecules 2 - 5, 7 and, 8. The structure of 6 was elucidated by extensive spectroscopic analyses and DFT calculations of the NMR and ECD data. All the compounds (2 - 8) were evaluated for their cytotoxic potential against a panel of eight cancer cell lines. Compounds 4, 5, 7, and 8 showed pronounced in vitro cytotoxic activity with IC50 values ranging from 5.6 to 60 μM. Out of the active molecules, compounds 4, and 7 were found to be comparable to that of the parent molecule 1 on the inhibition of almost all the tested cancer cell lines.


Protein dynamics. Direct observation of hierarchical protein dynamics.
One of the fundamental challenges of physical biology is to understand the relationship between protein dynamics and function. At physiological temperatures, functional motions arise from the complex interplay of thermal motions of proteins and their environments. Here, we determine the hierarchy in the protein conformational energy landscape that underlies these motions, based on a series of temperature-dependent magic-angle spinning multinuclear nuclear-magnetic-resonance relaxation measurements in a hydrated nanocrystalline protein. The results support strong coupling between protein and solvent dynamics above 160 kelvin, with fast solvent motions, slow protein side-chain motions, and fast protein backbone motions being activated consecutively. Low activation energy, small-amplitude local motions dominate at low temperatures, with larger-amplitude, anisotropic, and functionally relevant motions involving entire peptide units becoming dominant at temperatures above 220 kelvin.


Steady State Vapor Bubble in Pool Boiling.
Boiling, a dynamic and multiscale process, has been studied for several decades; however, a comprehensive understanding of the process is still lacking. The bubble ebullition cycle, which occurs over millisecond time-span, makes it extremely challenging to study near-surface interfacial characteristics of a single bubble. Here, we create a steady-state vapor bubble that can remain stable for hours in a pool of sub-cooled water using a femtosecond laser source. The stability of the bubble allows us to measure the contact-angle and perform in-situ imaging of the contact-line region and the microlayer, on hydrophilic and hydrophobic surfaces and in both degassed and regular (with dissolved air) water. The early growth stage of vapor bubble in degassed water shows a completely wetted bubble base with the microlayer, and the bubble does not depart from the surface due to reduced liquid pressure in the microlayer. Using experimental data and numerical simulations, we obtain permissible range of maximum heat transfer coefficient possible in nucleate boiling and the width of the evaporating layer in the contact-line region. This technique of creating and measuring fundamental characteristics of a stable vapor bubble will facilitate rational design of nanostructures for boiling enhancement and advance thermal management in electronics.


Predictors for health related quality of life in persons 65 years or older with chronic heart failure.
A main goal in nursing care of persons with chronic heart failure (HF) is to strengthen their health related quality of life (HRQoL). This presupposes knowledge about the relation between heart failure and HRQoL. Existing studies have shown incongruent results about whether HRQoL is affected differently depending on age or sex of elderly persons with chronic HF. This study aimed to investigate if age, sex, disease severity, comorbidity and living conditions predict health related quality of life among persons 65 years or older with chronic HF. The study included a sample of 357 persons. HRQoL was measured by the Minnesota Living with Heart Failure Questionnaire and the Short Form-12 Health Survey Questionnaire. Multiple regression analyses were performed to analyse the relation between the predictors and HRQoL. The main finding was that self-rated disease severity was strongly associated with HRQoL, but also age, sex, diabetes and respiratory diseases was associated with some of the dimensions of HRQoL. Interventions aimed at delaying the progress of the disease, assist persons' to cope with the disease and maintain the domains of HRQoL that are still feasible could be important to improve HRQoL in elderly persons with chronic HF.


Classical homeopathy in the treatment of cancer patients--a prospective observational study of two independent cohorts.
Many cancer patients seek homeopathy as a complementary therapy. It has rarely been studied systematically, whether homeopathic care is of benefit for cancer patients. We conducted a prospective observational study with cancer patients in two differently treated cohorts: one cohort with patients under complementary homeopathic treatment (HG; n = 259), and one cohort with conventionally treated cancer patients (CG; n = 380). For a direct comparison, matched pairs with patients of the same tumour entity and comparable prognosis were to be formed. Main outcome parameter: change of quality of life (FACT-G, FACIT-Sp) after 3 months. Secondary outcome parameters: change of quality of life (FACT-G, FACIT-Sp) after a year, as well as impairment by fatigue (MFI) and by anxiety and depression (HADS). HG: FACT-G, or FACIT-Sp, respectively improved statistically significantly in the first three months, from 75.6 (SD 14.6) to 81.1 (SD 16.9), or from 32.1 (SD 8.2) to 34.9 (SD 8.32), respectively. After 12 months, a further increase to 84.1 (SD 15.5) or 35.2 (SD 8.6) was found. Fatigue (MFI) decreased; anxiety and depression (HADS) did not change. CG: FACT-G remained constant in the first three months: 75.3 (SD 17.3) at t0, and 76.6 (SD 16.6) at t1. After 12 months, there was a slight increase to 78.9 (SD 18.1). FACIT-Sp scores improved significantly from t0 (31.0 - SD 8.9) to t1 (32.1 - SD 8.9) and declined again after a year (31.6 - SD 9.4). For fatigue, anxiety, and depression, no relevant changes were found. 120 patients of HG and 206 patients of CG met our criteria for matched-pairs selection. Due to large differences between the two patient populations, however, only 11 matched pairs could be formed. This is not sufficient for a comparative study. In our prospective study, we observed an improvement of quality of life as well as a tendency of fatigue symptoms to decrease in cancer patients under complementary homeopathic treatment. It would take considerably larger samples to find matched pairs suitable for comparison in order to establish a definite causal relation between these effects and homeopathic treatment.


Towards a functional definition of the mitochondrial human proteome.
The mitochondrial human proteome project (mt-HPP) was initiated by the Italian HPP group as a part of both the chromosome-centric initiative (C-HPP) and the ⿿biology and disease driven⿿ initiative (B/D-HPP). In recent years several reports highlighted how mitochondrial biology and disease are regulated by specific interactions with non-mitochondrial proteins. Thus, it is of great relevance to extend our present view of the mitochondrial proteome not only to those proteins that are encoded by or transported to mitochondria, but also to their interactors that take part in mitochondria functionality. Here, we propose a graphical representation of the functional mitochondrial proteome by retrieving mitochondrial proteins from the NeXtProt database and adding to the network their interactors as annotated in the IntAct database. Notably, the network may represent a reference to map all the proteins that are currently being identified in mitochondrial proteomics studies.


A metagenomic assessment of microbial eukaryotic diversity in the global ocean.
Surveying microbial diversity and function is accomplished by combining complementary molecular tools. Among them, metagenomics is a PCR free approach that contains all genetic information from microbial assemblages and is today performed at a relatively large scale and reasonable cost, mostly based on very short reads. Here, we investigated the potential of metagenomics to provide taxonomic reports of marine microbial eukaryotes. We prepared a curated database with reference sequences of the V4 region of 18S rDNA clustered at 97% similarity and used this database to extract and classify metagenomic reads. More than half of them were unambiguously affiliated to a unique reference whilst the rest could be assigned to a given taxonomic group. The overall diversity reported by metagenomics was similar to that obtained by amplicon sequencing of the V4 and V9 regions of the 18S rRNA gene, although either one or both of these amplicon surveys performed poorly for groups like Excavata, Amoebozoa, Fungi and Haptophyta. We then studied the diversity of picoeukaryotes and nanoeukaryotes using 91 metagenomes from surface down to bathypelagic layers in different oceans, unveiling a clear taxonomic separation between size fractions and depth layers. Finally, we retrieved long rDNA sequences from assembled metagenomes that improved phylogenetic reconstructions of particular groups. Overall, this study shows metagenomics as an excellent resource for taxonomic exploration of marine microbial eukaryotes.


A mouse model replicating hippocampal sparing cranial irradiation in humans: A tool for identifying new strategies to limit neurocognitive decline.
Cancer patients undergoing cranial irradiation are at risk of developing neurocognitive impairments. Recent evidence suggests that radiation-induced injury to the hippocampi could play an important role in this cognitive decline. As a tool for studying the mechanisms of hippocampal-dependent cognitive decline, we developed a mouse model replicating the results of the recent clinical RTOG 0933 study of hippocampal sparing whole-brain irradiation. We irradiated 16-week-old female C57BL/6J mice to a single dose of 10 Gy using either whole-brain irradiation (WBRT) or hippocampal sparing irradiation (HSI). These animals, as well as sham-irradiated controls, were subjected to behavioral/cognitive assessments distinguishing between hippocampal-dependent and hippocampal-independent functions. Irradiation was well tolerated by all animals and only limited cell death of proliferating cells was found within the generative zones. Animals exposed to WBRT showed significant deficits compared to sham-irradiated controls in the hippocampal-dependent behavioral task. In contrast, HSI mice did not perform significantly different from sham-irradiated mice (control group) and performed significantly better when compared to WBRT mice. This is consistent with the results from the RTOG 0933 clinical trial, and as such this animal model could prove a helpful tool for exploring new strategies for mitigating cognitive decline in cancer patients receiving cranial irradiation.


PhyloExplorer: a web server to validate, explore and query phylogenetic trees.
Many important problems in evolutionary biology require molecular phylogenies to be reconstructed. Phylogenetic trees must then be manipulated for subsequent inclusion in publications or analyses such as supertree inference and tree comparisons. However, no tool is currently available to facilitate the management of tree collections providing, for instance: standardisation of taxon names among trees with respect to a reference taxonomy; selection of relevant subsets of trees or sub-trees according to a taxonomic query; or simply computation of descriptive statistics on the collection. Moreover, although several databases of phylogenetic trees exist, there is currently no easy way to find trees that are both relevant and complementary to a given collection of trees. We propose a tool to facilitate assessment and management of phylogenetic tree collections. Given an input collection of rooted trees, PhyloExplorer provides facilities for obtaining statistics describing the collection, correcting invalid taxon names, extracting taxonomically relevant parts of the collection using a dedicated query language, and identifying related trees in the TreeBASE database. PhyloExplorer is a simple and interactive website implemented through underlying Python libraries and MySQL databases. It is available at: http://www.ncbi.orthomam.univ-montp2.fr/phyloexplorer/ and the source code can be downloaded from: http://code.google.com/p/taxomanie/.


Greater nicotinic acetylcholine receptor density in smokers than in nonsmokers: a PET study with 2-18F-FA-85380.
Assays of human postmortem brain tissue have revealed that smokers have greater densities of high-affinity nicotinic acetylcholine receptors (nAChRs) in several brain regions than do nonsmokers or exsmokers. Quantitative PET imaging of nAChRs in humans has recently been reported using the alpha4beta2* subtype-specific radioligand 2-(18)F-FA-85380 (2FA). We used PET and 2FA to measure total volumes of distribution corrected for the free fraction of 2FA in plasma (V(T)/f(P)) in 10 nonsmokers and 6 heavy smokers (>14 cigarettes/d; abstinent for >36 h). Dynamic PET scans were performed over 8 h, commencing immediately after a bolus injection of 2FA. Anatomic sampling was performed on PET images that were coregistered to MR images acquired from each volunteer. Data were analyzed by Logan plots and by 1- and 2-tissue-compartment models using unbound, unmetabolized arterial 2FA concentration as the input function. All modeling methods yielded similar results. V(T)/f(P) was significantly higher in smokers than in nonsmokers in all brain regions tested, except the thalamus. We used measures of V(T)/f(P) and estimates of nondisplaceable volume of distribution and found 25%-200% higher values in smokers than in nonsmokers for the volume of distribution for the specific binding compartment in the frontal cortex, midbrain, putamen, pons, cerebellum, and corpus callosum. These findings were consistent with voxel-based analysis using statistical parametric mapping. Our findings suggest that PET with 2FA can be used to study the role of nicotine-induced upregulation of nAChRs in active smokers and during smoking cessation.


Managed care regulation in the States: the impact on physicians' practices and clinical autonomy.
While the states engaged in an extended period of adopting and revising laws regulating managed care during the 1990s, there has been to date only limited empirical assessment of the impacts of these laws. For this analysis, we constructed a data set using information on state laws combined with survey responses of physicians. We distinguish regulations with a typology based on whether they affect the context or content of care and the target group of the regulation (consumer or provider). Our findings indicate that the context of care appears to be more efficaciously regulated than the content of care. Provisions concerning consumer access and contractual relationships lead to greater reported physician ability to obtain referrals and services, improved quality of clinical interactions, and greater perceived clinical autonomy. Regulations intended to enhance professional autonomy are associated with lower reported levels of utilization constraints and higher reported quality of clinical interactions. In contrast, consumer protection provisions, including procedures for appeals from plan decisions, appear to have had little impact on most physicians' practices. Despite structural and legal constraints on the potential effectiveness of these regulations, state managed care legislation appears to have provided some protections against managed care restrictions on physicians' clinical autonomy.


Carbohydrate ingestion during exercise does not delay the onset of fatigue during submaximal cycle exercise.
The objective of this study was to evaluate the effect of the ingestion of carbohydrate (CHO, in the form of maltodextrin) or placebo (PLAC, in the form of gelatin) on the physical performance of cyclists during submaximal exercise until fatigue on an ergometric cycle. Nine volunteers exercised on 2 separate occasions at least 2 days apart. On each occasion, after 48 hours of a balanced diet, they pedaled at approximately 66% Vo2peak until fatigue. Every 15 minutes, 150 mL of water and 18 capsules, containing either 0.5 g of CHO or PLAC (approximately 0.13 g x kg(-1) of body weight), were ingested in accordance with a double-blind, randomized protocol. The results show that after 40% of total exercise time, blood glucose levels in the CHO test returned to baseline levels. However, in the PLAC trial these levels failed to return to baseline levels, remaining lower than levels recorded in the CHO test after 60% of total exercise time. Despite these results, CHO ingestion failed to delay the onset of fatigue (CHO: 91.8 +/- 10.1 minutes vs. PLAC: 93.3 +/- 16.1 minutes; p = 0.87). In practical terms, coaches and trainers should consider that CHO ingestion in previously fed users does not delay the onset of fatigue during submaximal cycle exercise.


Lanthanide-doped upconversion nano-bioprobes: electronic structures, optical properties, and biodetection.
Lanthanide-doped upconversion nanoparticles (UCNPs) have attracted considerable interest due to their superior physicochemical features, such as large anti-Stokes shifts, low autofluorescence background, low toxicity and high penetration depth, which make them extremely suitable for use as alternatives to conventional downshifting luminescence bioprobes like organic dyes and quantum dots for various biological applications. A fundamental understanding of the photophysics of lanthanide-doped UCNPs is of vital importance for discovering novel optical properties and exploring their new applications. In this review, we focus on the most recent advances in the development of lanthanide-doped UCNPs as potential luminescent nano-bioprobes by means of our customized lanthanide photophysics measurement platforms specially designed for upconversion luminescence, which covers from their fundamental photophysics to bioapplications, including electronic structures (energy levels and local site symmetry of emitters), excited-state dynamics, optical property designing, and their promising applications for in vitro biodetection of tumor markers. Some future prospects and efforts towards this rapidly growing field are also envisioned.


Incidence of dsRNA mycoviruses in a collection of Aspergillus fumigatus isolates.
A collection of clinical and environmental isolates of the opportunistic human pathogen, Aspergillus fumigatus, were screened for the presence of mycoviruses and 6.6 % of 366 isolates contained dsRNA segments ranging in size from ~1.0 to 4.0 kbp. The dsRNAs were categorised into three different groups comprising bipartite dsRNAs, quadripartite dsRNAs, representative isolates of which have both been sequenced, and an uncharacterised mycovirus, whose genome apparently consists of four dsRNAs 1-2.5 kbp in size. Here, we describe dsRNA incidence in the A. fumigatus isolates examined, their provenance and also note that on occasion individual isolates were infected with two groups of different dsRNAs.