Camera Stabilization in 360° Videos and Its Impact on Cyber Sickness, Environmental Perceptions, and Psychophysiological Responses to a Simulated Nature Walk: A Single-Blinded Randomized Trial.
Immersive virtual environments (IVEs) technology has emerged as a valuable tool to environmental psychology research in general, and specifically to studies of human-nature interactions. However, virtual reality is known to induce cyber sickness, which limits its application and highlights the need for scientific strategies to optimize virtual experiences. In this study, we assessed the impact of improved camera stability on cyber sickness, presence, and psychophysiological responses to a simulated nature walk. In a single-blinded trial, 50 participants were assigned to watch, using a head-mounted display, one of two 10-min 360° videos showing a first-person nature walk: one video contained small-magnitude scene oscillations associated with cameraman locomotion, while in the other video, the oscillations were drastically reduced thanks to an electric stabilizer and a dolly. Measurements of cyber sickness (in terms of both occurrence and severity of symptoms), perceptions of the IVE (presence and perceived environmental restorativeness), and indicators of psychophysiological responses [affect, enjoyment, and heart rate (HR)] were collected before and/or after the exposure. Compared to the low-stability (LS) condition, in the high-stability (HS) condition, participants reported lower severity of cyber sickness symptoms. The delta values for pre-post changes in affect for the LS video revealed a deterioration of participants' affect profile with a significant increase in ratings of negative affect and fatigue, and decrease in ratings of positive affect. In contrast, there were no pre-post changes in affect for the HS video. No differences were found between the HS and LS conditions with respect to presence, perceived environmental restorativeness, enjoyment, and HR. Cyber sickness was significantly correlated with all components of affect and enjoyment, but not with presence, perceived environmental restorativeness, or HR. These findings demonstrate that improved camera stability in 360° videos is crucial to reduce cyber sickness symptoms and negative affective responses in IVE users. The lack of associations between improved stability and presence, perceived environmental restorativeness, and HR suggests that other aspects of IVE technology must be taken into account in order to improve virtual experiences of nature.


Does regional loss of bone density explain low trauma distal forearm fractures in men (the Mr F study)?
The pathogenesis of low trauma wrist fractures in men is not fully understood. This study found that these men have lower bone mineral density at the forearm itself, as well as the hip and spine, and has shown that forearm bone mineral density is the best predictor of wrist fracture. Men with distal forearm fractures have reduced bone density at the lumbar spine and hip sites, an increased risk of osteoporosis and a higher incidence of further fractures. The aim of this case-control study was to investigate whether or not there is a regional loss of bone mineral density (BMD) at the forearm between men with and without distal forearm fractures. Sixty-one men with low trauma distal forearm fracture and 59 age-matched bone healthy control subjects were recruited. All subjects underwent a DXA scan of forearm, hip and spine, biochemical investigations, health questionnaires, SF-36v2 and Fracture Risk Assessment Tool (FRAX). The non-fractured arm was investigated in subjects with fracture and both forearms in control subjects. BMD was significantly lower at the ultradistal forearm in men with fracture compared to control subjects, in both the dominant (mean (SD) 0.386 g/cm2 (0.049) versus 0.436 g/cm2 (0.054), p < 0.001) and non-dominant arm (mean (SD) 0.387 g/cm2 (0.060) versus 0.432 g/cm2 (0.061), p = 0.001). Fracture subjects also had a significantly lower BMD at hip and spine sites compared with control subjects. Logistic regression analysis showed that the best predictor of forearm fracture was ultradistal forearm BMD (OR = 0.871 (0.805-0.943), p = 0.001), with the likelihood of fracture decreasing by 12.9% for every 0.01 g/cm2 increase in ultradistal forearm BMD. Men with low trauma distal forearm fracture have significantly lower regional BMD at the ultradistal forearm, which contributes to an increased forearm fracture risk. They also have generalised reduction in BMD, so that low trauma forearm fractures in men should be considered as indicator fractures for osteoporosis.


Structural Basis for Fluorescence Activation by Pepper RNA.
Pepper is a fluorogenic RNA aptamer tag that binds to a variety of benzylidene-cyanophenyl (HBC) derivatives with tight affinity and activates their fluorescence. To investigate how Pepper RNA folds to create a binding site for HBC, we used antibody-assisted crystallography to determine the structures of Pepper bound to HBC530 and HBC599 to 2.3 and 2.7 Å resolutions, respectively. The structural data show that Pepper folds into an elongated structure and organizes nucleotides within an internal bulge to create the ligand binding site, assisted by an out-of-plane platform created by tertiary interactions with an adjacent bulge. As predicted from a lack of K+ dependence, Pepper does not use a G-quadruplex to form a binding pocket for HBC. Instead, Pepper uses a unique base-quadruple·base-triple stack to sandwich the ligand with a U·G wobble pair. Site-bound Mg2+ ions support ligand binding structurally and energetically. This research provides insight into the structural features that allow the Pepper aptamer to bind HBC and show how Pepper's function may expand to allow the in vivo detection of other small molecules and metals.


Explaining Pharmacy Students' Dispensing Intentions in Substance Abuse-Related Gray Areas Using the Theory of Planned Behavior.
Objective. To examine the extent to which theory of planned behavior (TPB) constructs and demographic characteristics explain pharmacy students' dispensing intentions in ethically or legally gray areas involving potential substance misuse or abuse. Methods. Two cohorts of third-year Doctor of Pharmacy (PharmD) students (n=159) were provided with five written cases describing common "gray area" dispensing scenarios in community practice involving medications and devices with potential for misuse or abuse (eg, long-term buprenorphine maintenance prescription without evidence of tapering, early refill of a narcotic for an out-of-town patient, non-prescription sale of pseudoephedrine). Students completed a 12-item survey instrument for each case. Items assessed whether the student would dispense the medication or device in the given scenario, how many times in 10 similar scenarios the student would dispense the medication or device, attitudes regarding dispensing, and subjective norm and perceived behavioral control beliefs. Results. Wide variation in the percentages of students who would dispense the medications or devices was noted across the five scenarios (14% in the buprenorphine scenario to 61% in the pseudoephedrine scenario). Attitude scores significantly predicted dispensing decisions in all scenarios (p<.001), whereas subjective norm and perceived behavioral control beliefs were significant predictors of dispensing only in select case scenarios. Gender and community pharmacy work experience did not consistently predict dispensing intentions. Conclusion. Student attitudes consistently predicted intent to dispense across five gray practice scenarios. These findings can be used to inform development of educational interventions that influence students' attitudes and self-awareness in community practice decision-making scenarios involving potential substance misuse or abuse.


Hibernation as a far-reaching program for the modulation of RNA transcription.
In eukaryotic cells, pre-mRNAs undergo several transformation steps to generate mature mRNAs ready to be exported to the cytoplasm. The molecular and structural apparatus for mRNA production is generally able to promptly respond to variations of metabolic demands. Hibernating mammals, which periodically enter a hypometabolic state, represent an interesting physiological model to investigate the adaptive morpho-functional modifications of the pre-mRNA transcriptional and processing machinery under extreme metabolic conditions. In this study, the subnuclear distribution of some transcriptional, splicing, and cleavage factors was investigated by ultrastructural immunocytochemistry in cell nuclei of the liver (a highly metabolizing organ involved in multiple regulatory functions) and the brown adipose tissue (responsible for nonshivering thermogenesis) from euthermic, hibernating, and arousing hazel dormice (Muscardinus avellanarius). Our observations demonstrate that, during hibernation, transcriptional activity significantly decreases and pre-mRNA processing factors undergo an intranuclear redistribution moving to domains usually devoid of such molecules; moreover, in hepatocytes, there is a preferential accumulation of pre-mRNAs at the splicing stage, whereas, in brown adipocytes, pre-mRNAs are mainly stored at the cleavage stage. Upon arousal, the pre-mRNAs at the cleavage stage are immediately utilized, while the maturation of pre-mRNAs at the splicing stage seems to be restored before transcription had taken place. Our data suggest a programmed intranuclear reorganization of the RNA maturation machinery aimed at efficiently and rapidly restoring the pre-mRNA processing, and, consequently, the specific cellular activities upon arousal. Once again natural hibernation appears as a highly programmed hypometabolic state rather than a simple fall of metabolic and physiological functions.


Stereotype formation: biased by association.
We propose that biases in attitude and stereotype formation might arise as a result of learned differences in the extent to which social groups have previously been predictive of behavioral or physical properties. Experiments 1 and 2 demonstrate that differences in the experienced predictiveness of groups with respect to evaluatively neutral information influence the extent to which participants later form attitudes and stereotypes about those groups. In contrast, Experiment 3 shows no influence of predictiveness when using a procedure designed to emphasize the use of higher level reasoning processes, a finding consistent with the idea that the root of the predictiveness bias is not in reasoning. Experiments 4 and 5 demonstrate that the predictiveness bias in formation of group beliefs does not depend on participants making global evaluations of groups. These results are discussed in relation to the associative mechanisms proposed by Mackintosh (1975) to explain similar phenomena in animal conditioning and associative learning.


Highly potent oxathiin carboxanilide derivatives with efficacy against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus isolates.
The structure-activity relationships of a series of compounds related to the nonnucleoside reverse transcriptase (RT) inhibitor (NNRTI) oxathiin carboxanilide have been described (R. W. Buckheit, Jr., T. L. Kinjerski, V. Fliakas-Boltz, J. D. Russell, T. L. Stup, L. A. Pallansch, W. G. Brouwer, D. C. Dao, W. A. Harrison, R. J. Schultz, J. P. Bader, and S. S. Yang, Antimicrob. Agents Chemother. 39:2718-2727, 1996). From these studies, the furanyl-containing analog UC10 was identified as the most potent inhibitor of human immunodeficiency virus type 1 (HIV-1) replication and a promising candidate for further development. Three new UC analogs (UC040, UC82, and UC781) have been determined to inhibit laboratory-derived and low-passage-number, primary virus isolates at low nanomolar concentrations in both established and fresh human cells. Each of the compounds synergistically interacted with the nucleoside analogs zidovudine, dideoxyinosine, dideoxycytosine, and lamivudine to inhibit HIV-1 replication. As a group, the UC compounds were found to be less active against viruses with the L100I, K103N, and Y181C amino acid changes in the RT and, upon in vitro selection, yielded resistant virus with the Y181C mutation in the RT. The most potent of the three new compounds, UC781, contains a furanyl side chain, similar to UC10, but differs in having an extended ether side chain instead of an oxime chain. The broad therapeutic index of UC781 (>62,000) resulted in effective inhibition of NNRTI-resistant virus isolates at high nanomolar concentrations. Furthermore, UC781 and the NNRTI costatolide were able to synergistically inhibit HIV-1 replication when used in combination, suggesting that UC781 may interact with the RT differently than the other UC analogs. The favorable anti-HIV properties of the UC compounds suggest they should be considered for further clinical development.


Effect of acidosis on contractile system in skinned fibers of hypertrophied rat heart.
Hypertrophied hearts have enhanced susceptibility to ischemia-induced contractile dysfunction. To explore the mechanisms of this phenomenon, we studied the effect of acidosis on the Ca2+ sensitivity of the contractile proteins and on Ca2+ accumulation by the sarcoplasmic reticulum (SR) in chemically (saponin) skinned cardiac fibers obtained from normal and pressure-overloaded hypertrophied rat left ventricles. Left ventricular pressure overload was induced by partial ligation of the abdominal aorta 6-8 wk before study. Age- and weight-matched normal rats served as controls. Pressure overload increased the left ventricular weight-to-body weight ratio by 48%. Reduction in pH shifted the pCa-tension curve to the right similarly in normal and hypertrophied preparations, and there was no difference in pCa-tension relationship at pH 7.0 or 6.5 between the two groups. However, reducing the pH of 1 microM Ca2(+)-loading solution from 7.0 to 6.5 decreased the amount of Ca2+ accumulated in the SR to 66.2 +/- 3.0% in normal fibers and 43.2 +/- 4.0% in hypertrophied fibers (P less than 0.01). We conclude that the enhanced susceptibility of hypertrophied hearts to ischemia-induced diastolic dysfunction may be partly explained by the greater depressing effect of acidosis on Ca2+ accumulation by the SR.


Rats with a missense mutation in Atm display neuroinflammation and neurodegeneration subsequent to accumulation of cytosolic DNA following unrepaired DNA damage.
Mutations in the ataxia-telangiectasia (A-T)-mutated (ATM) gene give rise to the human genetic disorder A-T, characterized by immunodeficiency, cancer predisposition, and neurodegeneration. Whereas a series of animal models recapitulate much of the A-T phenotype, they fail to present with ataxia or neurodegeneration. We describe here the generation of an Atm missense mutant [amino acid change of leucine (L) to proline (P) at position 2262 (L2262P)] rat by intracytoplasmic injection (ICSI) of mutant sperm into oocytes. Atm-mutant rats (AtmL2262P/L2262P ) expressed low levels of ATM protein, suggesting a destabilizing effect of the mutation, and had a significantly reduced lifespan compared with Atm+/+ Whereas these rats did not show cerebellar atrophy, they succumbed to hind-limb paralysis (45%), and the remainder developed tumors. Closer examination revealed the presence of both dsDNA and ssDNA in the cytoplasm of cells in the hippocampus, cerebellum, and spinal cord of AtmL2262P/L2262P rats. Significantly increased levels of IFN-β and IL-1β in all 3 tissues were indicative of DNA damage induction of the type 1 IFN response. This was further supported by NF-κB activation, as evidenced by p65 phosphorylation (P65) and translocation to the nucleus in the spinal cord and parahippocampus. Other evidence of neuroinflammation in the brain and spinal cord was the loss of motor neurons and the presence of increased activation of microglia. These data provide support for a proinflammatory phenotype that is manifested in the Atm mutant rat as hind-limb paralysis. This mutant represents a useful model to investigate the importance of neuroinflammation in A-T.


Major transcriptional changes observed in the Fulani, an ethnic group less susceptible to malaria.
The Fulani ethnic group has relatively better protection from Plasmodium falciparum malaria, as reflected by fewer symptomatic cases of malaria, lower infection rates, and lower parasite densities compared to sympatric ethnic groups. However, the basis for this lower susceptibility to malaria by the Fulani is unknown. The incidence of classic malaria resistance genes are lower in the Fulani than in other sympatric ethnic populations, and targeted SNP analyses of other candidate genes involved in the immune response to malaria have not been able to account for the observed difference in the Fulani susceptibility to P.falciparum. Therefore, we have performed a pilot study to examine global transcription and DNA methylation patterns in specific immune cell populations in the Fulani to elucidate the mechanisms that confer the lower susceptibility to P.falciparum malaria. When we compared uninfected and infected Fulani individuals, in contrast to uninfected and infected individuals from the sympatric ethnic group Mossi, we observed a key difference: a strong transcriptional response was only detected in the monocyte fraction of the Fulani, where over 1000 genes were significantly differentially expressed upon P.falciparum infection.


Self-tolerance curtails the B cell repertoire to microbial epitopes.
Immunological tolerance removes or inactivates self-reactive B cells, including those that also recognize cross-reactive foreign antigens. Whereas a few microbial pathogens exploit these "holes" in the B cell repertoire by mimicking host antigens to evade immune surveillance, the extent to which tolerance reduces the B cell repertoire to foreign antigens is unknown. Here, we use single-cell cultures to determine the repertoires of human B cell antigen receptors (BCRs) before (transitional B cells) and after (mature B cells) the second B cell tolerance checkpoint in both healthy donors and in patients with systemic lupus erythematosus (SLE) . In healthy donors, the majority (~70%) of transitional B cells that recognize foreign antigens also bind human self-antigens (foreign+self), and peripheral tolerance halves the frequency of foreign+self-reactive mature B cells. In contrast, in SLE patients who are defective in the second tolerance checkpoint, frequencies of foreign+self-reactive B cells remain unchanged during maturation of transitional to mature B cells. Patterns of foreign+self-reactivity among mature B cells from healthy donors differ from those of SLE patients. We propose that immune tolerance significantly reduces the scope of the BCR repertoire to microbial pathogens and that cross-reactivity between foreign and self epitopes may be more common than previously appreciated.


A Bridge Over Turbulent Waters: Illustrating the Interaction Between Managerial Leaders and Facilitators When Implementing Research Evidence.
Emerging evidence focuses on the importance of the role of leadership in successfully transferring research evidence into practice. However, little is known about the interaction between managerial leaders and clinical leaders acting as facilitators (internal facilitators [IFs]) in this implementation process. To describe the interaction between managerial leaders and IFs and how this enabled or hindered the facilitation process of implementing urinary incontinence guideline recommendations in a local context in settings that provide long-term care to older people. Semistructured interviews with 105 managers and 22 IFs, collected for a realist process evaluation across four European countries informed this study. An interpretive data analysis unpacks interactions between managerial leaders and IFs. This study identified three themes that were important in the interactions between managerial leaders and IFs that could hinder or support the implementation process: "realising commitment"; "negotiating conditions"; and "encouragement to keep momentum going." The findings revealed that the continuous reciprocal relationships between IFs and managerial leaders influenced the progress of implementation, and could slow the process down or disrupt it. A metaphor of crossing a turbulent river by the "building of a bridge" emerged as one way of understanding the findings. Our findings illuminate a neglected area, the effects of relationships between key staff on implementing evidence into practice. Relational aspects of managerial and clinical leadership roles need greater consideration when planning guideline implementation and practice change. In order to support implementation, staff assigned as IFs as well as stakeholders like managers at all levels of an organisation should be engaged in realising commitment, negotiating conditions, and keeping momentum going. Thus, communication is crucial between all involved.


Plasmonic Nanopores for Trapping, Controlling Displacement, and Sequencing of DNA.
With the aim of developing a DNA sequencing methodology, we theoretically examine the feasibility of using nanoplasmonics to control the translocation of a DNA molecule through a solid-state nanopore and to read off sequence information using surface-enhanced Raman spectroscopy. Using molecular dynamics simulations, we show that high-intensity optical hot spots produced by a metallic nanostructure can arrest DNA translocation through a solid-state nanopore, thus providing a physical knob for controlling the DNA speed. Switching the plasmonic field on and off can displace the DNA molecule in discrete steps, sequentially exposing neighboring fragments of a DNA molecule to the pore as well as to the plasmonic hot spot. Surface-enhanced Raman scattering from the exposed DNA fragments contains information about their nucleotide composition, possibly allowing the identification of the nucleotide sequence of a DNA molecule transported through the hot spot. The principles of plasmonic nanopore sequencing can be extended to detection of DNA modifications and RNA characterization.


Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000.
Induction therapy for childhood acute lymphoblastic leukemia (ALL) traditionally includes prednisone; yet, dexamethasone may have higher antileukemic potency, leading to fewer relapses and improved survival. After a 7-day prednisone prephase, 3720 patients enrolled on trial Associazione Italiana di Ematologia e Oncologia Pediatrica and Berlin-Frankfurt-Münster (AIEOP-BFM) ALL 2000 were randomly selected to receive either dexamethasone (10 mg/m(2) per day) or prednisone (60 mg/m(2) per day) for 3 weeks plus tapering in induction. The 5-year cumulative incidence of relapse (± standard error) was 10.8 ± 0.7% in the dexamethasone and 15.6 ± 0.8% in the prednisone group (P < .0001), showing the largest effect on extramedullary relapses. The benefit of dexamethasone was partially counterbalanced by a significantly higher induction-related death rate (2.5% vs 0.9%, P = .00013), resulting in 5-year event-free survival rates of 83.9 ± 0.9% for dexamethasone and 80.8 ± 0.9% for prednisone (P = .024). No difference was seen in 5-year overall survival (OS) in the total cohort (dexamethasone, 90.3 ± 0.7%; prednisone, 90.5 ± 0.7%). Retrospective analyses of predefined subgroups revealed a significant survival benefit from dexamethasone only for patients with T-cell ALL and good response to the prednisone prephase (prednisone good-response [PGR]) (dexamethasone, 91.4 ± 2.4%; prednisone, 82.6 ± 3.2%; P = .036). In patients with precursor B-cell ALL and PGR, survival after relapse was found to be significantly worse if patients were previously assigned to the dexamethasone arm. We conclude that, for patients with PGR in the large subgroup of precursor B-cell ALL, dexamethasone especially reduced the incidence of better salvageable relapses, resulting in inferior survival after relapse. This explains the lack of benefit from dexamethasone in overall survival that we observed in the total cohort except in the subset of T-cell ALL patients with PGR. This trial was registered at www.clinicaltrials.gov (BFM: NCT00430118, AIEOP: NCT00613457).


Oxygen plasma exposure effects on indium oxide nanowire transistors.
In(2)O(3) nanowire transistors are fabricated with and without oxygen plasma exposure of various regions of the nanowire. In two-terminal devices, exposure of the channel region results in an increased conductance of the channel region. For In(2)O(3) nanowire transistors in which the source/drain regions are exposed to oxygen plasma, the mobility, on-off current ratio and subthreshold slope, are improved with respect to those of non-exposed devices. Simulations using a two-dimensional device simulator (MEDICI) show that improved device performance can be quantified in terms of changes in interfacial trap, shifts in fixed charge densities and the corresponding reduction in Schottky barrier height at the contacts.


Interactions between phosphatidylinositol 3-kinase and nitric oxide: explaining the paradox.
Nitric oxide (NO) and the many derivatives and reactive oxygen intermediates thereof are all molecules that are utilised by mammalian cells in the war against microbial pathogens and tumours. They are potentially toxic molecules and, with damage control being crucial, the production and metabolism of nitric oxide is a tightly regulated process. The duality of NO is well documented. On the one hand, beneficial effects include normal healing in the skin and intestinal mucosa, killing of certain bacteria, regulating T cell proliferation and differentiation (Th1 vs Th2), and regulating leukocyte recruitment, by affecting adhesion molecule expression. On the other hand, persistent high levels of NO can lead to the production of toxic metabolites (peroxynitrite and hydroxyls), which can have detrimental effects, such as increased microvascular and epithelial permeability, increased oxidative stress (which can damage DNA), and damage to iron-sulphur proteins in mitochondria. NO has been reported to modulate its own production and the mechanisms involved in this self-regulation are being hotly pursued. The purpose of this review is to update recent intriguing advances in our understanding of the interaction of the phosphatidylinositol (PI) 3-kinase-dependent signal transduction pathway in regulating the activity of the enzymes that generate NO, namely, the nitric oxide synthases.


Engineering GPCR signaling pathways with RASSLs.
We are creating families of designer G protein-coupled receptors (GPCRs) to allow for precise spatiotemporal control of GPCR signaling in vivo. These engineered GPCRs, called receptors activated solely by synthetic ligands (RASSLs), are unresponsive to endogenous ligands but can be activated by nanomolar concentrations of pharmacologically inert, drug-like small molecules. Currently, RASSLs exist for the three major GPCR signaling pathways (G(s), G(i) and G(q)). We review these advances here to facilitate the use of these powerful and diverse tools.


Impact of the COVID-19 pandemic on interventional cardiology fellowship training in the New York metropolitan area: A perspective from the United States epicenter.
The healthcare burden posed by the coronavirus disease 2019 (COVID-19) pandemic in the New York Metropolitan area has necessitated the postponement of elective procedures resulting in a marked reduction in cardiac catheterization laboratory (CCL) volumes with a potential to impact interventional cardiology (IC) fellowship training. We conducted a web-based survey sent electronically to 21 Accreditation Council for Graduate Medical Education accredited IC fellowship program directors (PDs) and their respective fellows. Fourteen programs (67%) responded to the survey and all acknowledged a significant decrease in CCL procedural volumes. More than half of the PDs reported part of their CCL being converted to inpatient units and IC fellows being redeployed to COVID-19 related duties. More than two-thirds of PDs believed that the COVID-19 pandemic would have a moderate (57%) or severe (14%) adverse impact on IC fellowship training, and 21% of the PDs expected their current fellows' average percutaneous coronary intervention (PCI) volume to be below 250. Of 25 IC fellow respondents, 95% expressed concern that the pandemic would have a moderate (72%) or severe (24%) adverse impact on their fellowship training, and nearly one-fourth of fellows reported performing fewer than 250 PCIs as of March 1st. Finally, roughly one-third of PDs and IC fellows felt that there should be consideration of an extension of fellowship training or a period of early career mentorship after fellowship. The COVID-19 pandemic has caused a significant reduction in CCL procedural volumes that is impacting IC fellowship training in the NY metropolitan area. These results should inform professional societies and accreditation bodies to offer tailored opportunities for remediation of affected trainees.


Trends in the utilization of youth primary healthcare services and psychological distress.
Psychological distress among young people is increasing in Northern Europe. According to established healthcare utilization theory, this will create a greater need for youth primary healthcare and subsequently lead to more help-seeking behavior by distressed young people. The aim of this study was to investigate the association between the use of youth primary healthcare services and psychological distress in times of increasing mental health problems and increased service need. This study consisted of five waves of repeated annual cross-sectional data collected from young people (aged 13-19) living in Norway between 2014 and 2018 (n = 368,579). Population-weighted and design-adjusted generalized linear regression with a log-link was used to examine the use of youth primary healthcare services over time. We found that a large proportion of young people use primary healthcare services and that young people with high levels of psychological distress use primary healthcare services twice as much as their peers with low levels of psychological distress. In addition, between 2014 and 2018 both psychological distress and primary healthcare service utilization increased: psychological distress increased by 5% and total primary healthcare service use increased by 500 consultations per 1000 young people. Overall, psychological distress had a conditional association with youth primary healthcare service use and could account for between 16 and 66% of the change in the use of services between 2014 and 2018, depending on the service type. However, the absolute increase seen in the use of primary healthcare services was mainly driven by young people with low levels of psychological distress as opposed to young people with high psychological distress. This suggest a converging trend. Our findings suggest that there might be serious barriers between need and help-seeking behavior for young people with high levels of psychological distress and that the pattern of utilization among young people with lower distress may indicate overuse, possibly as an inadvertent consequence of a newly introduced school absence policy. While further research is needed to confirm these findings, our work may inform healthcare providers and policy makers about primary healthcare utilization trends among young people.


To sleep or not to sleep: the ecology of sleep in artificial organisms.
All animals thus far studied sleep, but little is known about the ecological factors that generate differences in sleep characteristics across species, such as total sleep duration or division of sleep into multiple bouts across the 24-hour period (i.e., monophasic or polyphasic sleep activity). Here we address these questions using an evolutionary agent-based model. The model is spatially explicit, with food and sleep sites distributed in two clusters on the landscape. Agents acquire food and sleep energy based on an internal circadian clock coded by 24 traits (one for each hour of the day) that correspond to "genes" that evolve by means of a genetic algorithm. These traits can assume three different values that specify the agents' behavior: sleep (or search for a sleep site), eat (or search for a food site), or flexibly decide action based on relative levels of sleep energy and food energy. Individuals with higher fitness scores leave more offspring in the next generation of the simulation, and the model can therefore be used to identify evolutionarily adaptive circadian clock parameters under different ecological conditions. We systematically varied input parameters related to the number of food and sleep sites, the degree to which food and sleep sites overlap, and the rate at which food patches were depleted. Our results reveal that: (1) the increased costs of traveling between more spatially separated food and sleep clusters select for monophasic sleep, (2) more rapid food patch depletion reduces sleep times, and (3) agents spend more time attempting to acquire the "rarer" resource, that is, the average time spent sleeping is positively correlated with the number of food patches and negatively correlated with the number of sleep patches. "Flexible" genes, in general, do not appear to be advantageous, though their arrangements in the agents' genome show characteristic patterns that suggest that selection acts on their distribution. Collectively, the output suggests that ecological factors can have striking effects on sleep patterns. Moreover, our results demonstrate that a simple model can produce clear and sensible patterns, thus allowing it to be used to investigate a wide range of questions concerning the ecology of sleep. Quantitative data presently are unavailable to test the model predictions directly, but patterns are consistent with comparative evidence from different species, and the model can be used to target ecological factors to investigate in future research.


Evidence of epistasis between interleukin 1 and selenoprotein-S with susceptibility to rheumatoid arthritis.
Selenoprotein-S (SELS) is involved in the stress response within the endoplasmic reticulum (ER) and inflammation. Recently, promoter variants in the SELS gene were shown to be associated with plasma levels of interleukin (IL)6, IL1beta and tumour necrosis factor (TNF). It was hypothesised that these variants could influence rheumatoid arthritis (RA) susceptibility and may interact with functional single nucleotide polymorphisms (SNPs) in the genes for IL1, IL6 and TNF. Genotyping was performed in 988 unrelated healthy controls and 965 patients with RA. Stratified analysis was used to test for interactions. Single gene effects and evidence of epistasis were investigated using the Mantel-Haenszel (M-H) test and the linkage disequilibrium (LD)-based statistic. No association of SELS -105 genotype and RA susceptibility was detected. Stratification of SELS -105 genotypes by IL1 -511 genotypes showed that the disease risk (comparing AA/GA to GG at the SELS -105 locus) in individuals with the GG/AG genotype at the IL1beta -511 locus was significantly lower than that in individuals having the AA genotype at the IL1beta -511 locus (odds ratio (OR): 0.9 and 2.3, respectively; p = 0.004 by M-H test). Significant epistasis was also detected using the LD-based statistic (p = <0.001). No interaction was observed between SELS -105 and IL6 or TNF variants. Our results reveal evidence of strong epistasis in two genes in the IL1 production pathway and highlight the potential importance of gene-gene interactions in the pathogenesis of RA.


Prescribing and partnership with patients.
There have been widespread changes in society and the roles of professionals. This change is also reflected in health care, where there is now acceptance of the need to involve patients in decision making. In prescribing specifically, the concordance agenda was developed alongside these initiatives to encourage improved medication taking and reduce wastage. However the extent to which these partnerships are delivered in practice remains unclear. This paper explores some of the issues to be considered when preparing patients and professionals for partnership and summarizes the limited evidence of barriers to, and benefits of, this approach. Firstly patients must be given the confidence, skills and knowledge to be partners. They need information about medicines, provided in ways known to be acceptable to them. Likewise professionals may need new skills to be partners. They need to understand the patient agenda and may need training and support to change the ways in which they consult with patients. There are also practical issues such as the perceived increase in time taken when consulting in partnership mode, room layout, computer interfaces and record keeping. Health care professionals other than doctors are also expected to behave in partnership mode, whether this is as prescribers in their own right or in supporting the prescribing of others. Whilst much has been claimed for the benefit of partnership approaches, hard evidence is limited. However whilst there is still much more to understand there will be no going back to the paternalistic model of the mid 20th century.


[Management of hepatitis B virus and hepatitis C virus infection in chronic kidney failure].
Chronic infections by hepatitis B (HBV) and C virus (HCV) result in diagnosis and therapeutic issues in dialysis and kidney recipients patients. The exposure to nosocomial, including blood transfusion, risk explains the high prevalence of HBV and HCV infection in this setting. Chronic infection reduces the survival of both patients and allografts, including a specific risk of de novo glomerulonephritis. Cirrhosis was considered as a contra-indication to renal transplantation given the high risk of decompensation and death, questionning the indication of a combined liver and kidney transplantation. Thus, it is mandatory to screen HBV and HCV markers in all dialysis patients, whether or not they are candidates to transplantation. Liver biopsy allows evaluating the severity of the liver disease since the noninvasive markers of fibrosis appear to be less accurate in "renal" patients than in the general population and to better define antiviral therapeutic indications. HCV treatment was mainly based on pegylated interferon α (and low doses of ribavirin), which is contra-indicated in kidney recipients given the risk of graft rejection; HCV treatment is now based on the use of oral direct acting antivirals, which are very potent and well tolerated. HBV replication is now easily suppressed by second-generation nucleos(t)tidic analogues (entecavir and tenofovir), which will be indicated in all the dialysis patients with significant fibrosis (F2,3 or 4 according to the Metavir scoring system) and in any candidate to renal transplantation and to any HBsAg-positive kidney recipients. The best treatment remains preventive by anti-HBV vaccination for HBV and by the respect of universal hygiene rules for HCV.


Phytochemical analysis and biological evaluation of selected African propolis samples from Cameroon and Congo.
The objective of this study was the chemical analysis of four selected samples of African propolis (Congo and Cameroon) and their biological evaluation. Twenty-one secondary metabolites belonging to four different chemical groups were isolated from the 70% ethanolic extracts of propolis and their structures were elucidated on the basis of spectral evidence. Three triterpenes and two diprenyl-flavonoids were identified from Congo propolis, which has been investigated for the first time, while thirteen triterpenes, three diprenyl-flavonoids, two monoterpenic alcohols and one fatty acid ester have been identified from Cameroon propolis samples. To our knowledge, the identified diprenyl-flavonoids, as well as five of the isolated and determined triterpenes, are reported for the first time in propolis. Moreover, the total polyphenol content was estimated in all extracts and the antimicrobial activities of all four extracts were studied against six Gram-positive and -negative bacteria and three pathogenic fungi, showing an interesting antibacterial profile.


Generalized encoding and decoding operators for lattice-based associative memories.
During the 1990s Ritter, introduced a new family of associative memories based on lattice algebra instead of linear algebra. These memories provide unlimited storage capacity, unlike linear-correlation-based models. The canonical lattice-based memories, however, are susceptible to noise in the initial input data. In this brief, we present novel methods of encoding and decoding lattice-based memories using two families of ordered weighted average (OWA) operators. The result is a greater robustness to distortion in the initial input data, and a greater understanding of the effect of the choice of encoding and decoding operators on the behavior of the system, with the tradeoff that the time complexity for encoding is increased.


Oral selenium supplementation has no effect on prostate-specific antigen velocity in men undergoing active surveillance for localized prostate cancer.
The Nutritional Prevention of Cancer trial showed a 52% lower incidence of prostate cancer in men supplemented with selenium. As a result, our study was designed to assess whether selenium supplementation attenuates the progression of prostate cancer. A phase 2 randomized, double-blind, placebo-controlled clinical trial was conducted in men with localized nonmetastatic prostate cancer who had elected to forgo active treatment and be followed by active surveillance. A total of 140 men were randomized to placebo (n = 46), 200 microg/d (n = 47), or 800 microg/d (n = 47) selenium p.o. (as selenized yeast) and followed every 3 months for up to 5 years. Prostate-specific antigen (PSA) velocity was used as a marker of prostate cancer progression and was estimated using mixed-effects regression. Adjusting for age, body mass index, baseline selenium, smoking, baseline PSA, race, PSA method, and Gleason score, PSA velocities for the 200 microg/d and 800 microg/d treatment groups were not statistically significantly different from placebo (P = 0.32 and P = 0.61, respectively). In the highest quartile of baseline selenium, men supplemented with 800 microg selenium showed statistically significantly higher PSA velocity as compared with placebo (P = 0.018). Selenium supplementation did not show a protective effect on PSA velocity in subjects with localized prostate cancer. On the contrary, supplementation with high-dose selenium was observed to be a risk factor for increased PSA velocity in men with high baseline plasma selenium concentrations.


Development and in vitro evaluation of a drug delivery system based on chitosan-EDTA BBI conjugate.
In this study a (poly)peptide drug delivery system providing a protective effect towards serine pancreatic proteases was generated. Tablets containing insulin (3.3%), chitosan-EDTA (56.7%), chitosan-EDTA Bowman Birk Inhibitor (= BBI) conjugate (10%) and mannitol (30%) were homogenised in a mortar and compressed to tablets. The protective effect of this dosage form for the incorporated model drug was evaluated in vitro. Tablets were therefore incubated with an artificial intestinal fluid containing trypsin (1350 spectrophotometric BAEE units/ml), chymotrypsin (3.6 BTEE units/ml) and elastase (0.14 succinyl-Ala-Ala-Ala-p-nitroanilide units/ml) for 4.5 h at 37 degrees C. Following analysis of the dosage form demonstrated that 58.6+/-26.8% (mean +/- SD; n = 3) insulin in lateral parts and 44.4+/-12.4% (mean +/- SD: n = 3) insulin in inner parts of the swollen carrier-matrix were degraded, whereas insulin was completely metabolised in lateral parts and by 90.3+/-12.5% (mean +/- SD: n = 3) in inner parts of tablets without the chitosan-EDTA BBI conjugate. As chitosan-EDTA also provides a protective effect towards zinc-dependent proteases, the delivery system described in this study should therefore guarantee a protection towards the most abundant intestinal proteases. It might be a promising formulation for the peroral administration of peptide and protein drugs.


Intracranial hemorrhage.
Intracranial hemorrhage is a life-threatening condition, the outcome of which can be improved by intensive care. Intracranial hemorrhage may be spontaneous, precipitated by an underlying vascular malformation, induced by trauma, or related to therapeutic anticoagulation. The goals of critical care are to assess the proximate cause, minimize the risks of hemorrhage expansion through blood pressure control and correction of coagulopathy, and obliterate vascular lesions with a high risk of acute rebleeding. Simple bedside scales and interpretation of computed tomography scans assess the severity of neurological injury. Myocardial stunning and pulmonary edema related to neurological injury should be anticipated, and can usually be managed. Fever (often not from infection) is common and can be effectively treated, although therapeutic cooling has not been shown to improve outcomes after intracranial hemorrhage. Most functional and cognitive recovery takes place weeks to months after discharge; expected levels of functional independence (no disability, disability but independence with a device, dependence) may guide conversations with patient representatives. Goals of care impact mortality, with do-not-resuscitate status increasing the predicted mortality for any level of severity of intraparenchymal hemorrhage. Future directions include refining the use of bedside neuro-monitoring (electroencephalogram, invasive monitors), novel approaches to reduce intracranial hemorrhage expansion, minimizing vasospasm, and refining the assessment of quality of life to guide rehabilitation and therapy.


Proanthocyanidin from blueberry leaves suppresses expression of subgenomic hepatitis C virus RNA.
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. While searching for new natural anti-HCV agents in agricultural products, we found a potent inhibitor of HCV RNA expression in extracts of blueberry leaves when examined in an HCV subgenomic replicon cell culture system. This activity was observed in a methanol extract fraction of blueberry leaves and was purified by repeated fractionations in reversed-phase high-performance liquid chromatography. The final purified fraction showed a 63-fold increase in specific activity compared with the initial methanol extracts and was composed only of carbon, hydrogen, and oxygen. Liquid chromatography/mass-ion trap-time of flight analysis and butanol-HCl hydrolysis analysis of the purified fraction revealed that the blueberry leaf-derived inhibitor was proanthocyanidin. Furthermore, structural analysis using acid thiolysis indicated that the mean degree of polymerization of the purified proanthocyanidin was 7.7, consisting predominantly of epicatechin. Proanthocyanidin with a polymerization degree of 8 to 9 showed the greatest potency at inhibiting the expression of subgenomic HCV RNA. Purified proanthocyanidin showed dose-dependent inhibition of expression of the neomycin-resistant gene and the NS-3 protein gene in the HCV subgenome in replicon cells. While characterizing the mechanism by which proanthocyanidin inhibited HCV subgenome expression, we found that heterogeneous nuclear ribonucleoprotein A2/B1 showed affinity to blueberry leaf-derived proanthocyanidin and was indispensable for HCV subgenome expression in replicon cells. These data suggest that proanthocyanidin isolated from blueberry leaves may have potential usefulness as an anti-HCV compound by inhibiting viral replication.


Guilt and Proneness to Shame: Unethical Behaviour in Vulnerable and Grandiose Narcissism.
Narcissists are described as individuals with dysfunctional personality traits such as lack of psychological awareness and empathy. Theories of ethical behaviour assume that unethical actions trigger moral emotions of guilt and shame. Currently, there is a lack of knowledge on moral emotions as dispositional traits and their potential influences on behaviour in individuals with narcissistic traits. The present study examined vulnerable and grandiose narcissism's differences in the propensity to experience guilt and shame as a proneness, across a range of personal transgressions. Guilt proneness was measured by negative evaluation of unethical behaviour, and whether this evaluation could influence reparation of tendencies of unethical action in vulnerable and grandiose narcissism. Shame proneness was investigated by negative evaluation of the self, and then whether the previous tendency could affect unethical decision making and behaviour (e.g., hiding), in vulnerable and grandiose narcissism. Two hundred and sixteen participants responded to the Guilt and Shame Proneness Scale, the Narcissistic Personality Inventory Scale and the Hypersensitive Narcissism Scale in an online questionnaire. Findings indicate that grandiose narcissism was negatively associated with guilt proneness, and the relation between the vulnerable narcissism and guilt proneness was negative. Additionally, the results confirm a negative association between grandiose narcissism and shame proneness, especially related to the subscale 'shame negative self-evaluation'. Furthermore, guilt and shame proneness explained 20% of the variance in vulnerable narcissism and 11% in grandiose narcissism. This research indicates that both vulnerable and grandiose narcissism have the tendency to make unethical decisions, and they are more likely to enact in unethical behaviour. These findings are relevant for the detection of narcissistic individual's propensity to act unethically in social context.


Methylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan.
Several pathways modulating longevity and stress resistance converge on translation by targeting ribosomal proteins or initiation factors, but whether this involves modifications of ribosomal RNA is unclear. Here, we show that reduced levels of the conserved RNA methyltransferase NSUN5 increase the lifespan and stress resistance in yeast, worms and flies. Rcm1, the yeast homologue of NSUN5, methylates C2278 within a conserved region of 25S rRNA. Loss of Rcm1 alters the structural conformation of the ribosome in close proximity to C2278, as well as translational fidelity, and favours recruitment of a distinct subset of oxidative stress-responsive mRNAs into polysomes. Thus, rather than merely being a static molecular machine executing translation, the ribosome exhibits functional diversity by modification of just a single rRNA nucleotide, resulting in an alteration of organismal physiological behaviour, and linking rRNA-mediated translational regulation to modulation of lifespan, and differential stress response.


Recent advances in understanding the ryanodine receptor calcium release channels and their role in calcium signalling.
The ryanodine receptor calcium release channel is central to cytoplasmic Ca 2+ signalling in skeletal muscle, the heart, and many other tissues, including the central nervous system, lymphocytes, stomach, kidney, adrenal glands, ovaries, testes, thymus, and lungs. The ion channel protein is massive (more than 2.2 MDa) and has a structure that has defied detailed determination until recent developments in cryo-electron microscopy revealed much of its structure at near-atomic resolution. The availability of this high-resolution structure has provided the most significant advances in understanding the function of the ion channel in the past 30 years. We can now visualise the molecular environment of individual amino acid residues that form binding sites for essential modulators of ion channel function and determine its role in Ca 2+ signalling. Importantly, the structure has revealed the structural environment of the many deletions and point mutations that disrupt Ca 2+ signalling in skeletal and cardiac myopathies and neuropathies. The implications are of vital importance to our understanding of the molecular basis of the ion channel's function and for the design of therapies to counteract the effects of ryanodine receptor-associated disorders.


Design and implementation of electronic health record common data elements for pediatric epilepsy: Foundations for a learning health care system.
Common data elements (CDEs) are standardized questions and answer choices that allow aggregation, analysis, and comparison of observations from multiple sources. Clinical CDEs are foundational for learning health care systems, a data-driven approach to health care focused on continuous improvement of outcomes. We aimed to create clinical CDEs for pediatric epilepsy. A multiple stakeholder group (clinicians, researchers, parents, caregivers, advocates, and electronic health record [EHR] vendors) developed clinical CDEs for routine care of children with epilepsy. Initial drafts drew from clinical epilepsy note templates, CDEs created for clinical research, items in existing registries, consensus documents and guidelines, quality metrics, and outcomes needed for demonstration projects. The CDEs were refined through discussion and field testing. We describe the development process, rationale for CDE selection, findings from piloting, and the CDEs themselves. We also describe early implementation, including experience with EHR systems and compatibility with the International League Against Epilepsy classification of seizure types. Common data elements were drafted in August 2017 and finalized in January 2020. Prioritized outcomes included seizure control, seizure freedom, American Academy of Neurology quality measures, presence of common comorbidities, and quality of life. The CDEs were piloted at 224 visits at 10 centers. The final CDEs included 36 questions in nine sections (number of questions): diagnosis (1), seizure frequency (9), quality of life (2), epilepsy history (6), etiology (8), comorbidities (2), treatment (2), process measures (5), and longitudinal history notes (1). Seizures are categorized as generalized tonic-clonic (regardless of onset), motor, nonmotor, and epileptic spasms. Focality is collected as epilepsy type rather than seizure type. Seizure frequency is measured in nine levels (all used during piloting). The CDEs were implemented in three vendor systems. Early clinical adoption included 1294 encounters at one center. We created, piloted, refined, finalized, and implemented a novel set of clinical CDEs for pediatric epilepsy.


De-DUFing the DUFs: Deciphering distant evolutionary relationships of Domains of Unknown Function using sensitive homology detection methods.
In the post-genomic era where sequences are being determined at a rapid rate, we are highly reliant on computational methods for their tentative biochemical characterization. The Pfam database currently contains 3,786 families corresponding to "Domains of Unknown Function" (DUF) or "Uncharacterized Protein Family" (UPF), of which 3,087 families have no reported three-dimensional structure, constituting almost one-fourth of the known protein families in search for both structure and function. We applied a 'computational structural genomics' approach using five state-of-the-art remote similarity detection methods to detect the relationship between uncharacterized DUFs and domain families of known structures. The association with a structural domain family could serve as a start point in elucidating the function of a DUF. Amongst these five methods, searches in SCOP-NrichD database have been applied for the first time. Predictions were classified into high, medium and low- confidence based on the consensus of results from various approaches and also annotated with enzyme and Gene ontology terms. 614 uncharacterized DUFs could be associated with a known structural domain, of which high confidence predictions, involving at least four methods, were made for 54 families. These structure-function relationships for the 614 DUF families can be accessed on-line at http://proline.biochem.iisc.ernet.in/RHD_DUFS/ . For potential enzymes in this set, we assessed their compatibility with the associated fold and performed detailed structural and functional annotation by examining alignments and extent of conservation of functional residues. Detailed discussion is provided for interesting assignments for DUF3050, DUF1636, DUF1572, DUF2092 and DUF659. This study provides insights into the structure and potential function for nearly 20 % of the DUFs. Use of different computational approaches enables us to reliably recognize distant relationships, especially when they converge to a common assignment because the methods are often complementary. We observe that while pointers to the structural domain can offer the right clues to the function of a protein, recognition of its precise functional role is still 'non-trivial' with many DUF domains conserving only some of the critical residues. It is not clear whether these are functional vestiges or instances involving alternate substrates and interacting partners.


An evaluation of health impact assessments in the United States, 2011-2014.
The Center for Community Health and Evaluation conducted a 3-year evaluation to assess results of health impact assessments (HIAs) in the United States and to identify elements critical for their success. The study used a retrospective, mixed-methods comparative case study design, including a literature review; site visits; interviews with investigators, stakeholders, and decision makers for 23 HIAs in 16 states that were completed from 2005 through 2013; and a Web-based survey of 144 HIA practitioners. Analysis of interviews with decision makers suggests HIAs can directly influence decisions in nonhealth-related sectors. HIAs may also influence changes beyond the decision target, build consensus and relationships among decision makers and their constituents, and give community members a stronger voice in decisions that affect them. Factors that may increase HIA success include care in choosing a project or policy to be examined' selecting an appropriate team to conduct the HIA; engaging stakeholders and decision makers throughout the process; crafting clear, actionable recommendations; delivering timely, compelling messages to appropriate audiences; and using multiple dissemination methods. Challenges to successful HIAs include underestimating the level of effort required, political changes during the conduct of the HIA, accessing relevant local data, engaging vulnerable populations, and following up on recommendations. Results of this study suggest HIAs are a useful tool to promote public health because they can influence decisions in nonhealth-related sectors, strengthen cross-sector collaborations, and raise awareness of health issues among decision makers.


Genetically encoded Ca2+ -sensor reveals details of porcine endothelial cell activation upon contact with human serum.
The activation of the endothelial surface in xenografts is still a poorly understood process and the consequences are unpredictable. The role of Ca2+ -messaging during the activation of endothelial cells is well recognized and routinely measured by synthetic Ca2+ -sensitive fluorophors. However, these compounds require fresh loading immediately before each experiment and in particular when grown in state-of-the-art 3D cell culture systems, endothelial cells are difficult to access with such sensors. Therefore, we developed transgenic pigs expressing a Ca2+ -sensitive protein and examined its principal characteristics. Primary transgenic endothelial cells stimulated by ATP showed a definite and short influx of Ca2+ into the cytosol, whereas exposure to human serum resulted in a more intense and sustained response. Surprisingly, not all endothelial cells reacted identically to a stimulus, rather activation took place in adjacent cells in a timely decelerated way and with distinct intensities. This effect was again more pronounced when cells were stimulated with human serum. Finally, we show clear evidence that antibody binding alone significantly activated endothelial cells, whereas antibody depletion dramatically reduced the stimulatory potential of serum. Transgenic porcine endothelial cells expressing a Ca2+ -sensor represent an interesting tool to dissect factors inducing activation of porcine endothelial cells after exposure to human blood or serum.


Role of N-terminal residues on folding and stability of C-phycoerythrin: simulation and urea-induced denaturation studies.
The conformational state of biliproteins can be determined by optical properties of the covalently linked chromophores. Recently determined crystal structure of truncated form of α-subunit of cyanobacterial phycoerythrin (αC-PE) from Phormidium tenue provides a new insight into the structure-function relationship of αC-PE. To compare their stabilities, we have measured urea-induced denaturation transitions of the full length αC-PE (FL-αC-PE) and truncated αC-PE (Tr-αC-PE) followed by observing changes in absorbance at 565 nm, fluorescence at 350 and 573 nm, and circular dichroism at 222 nm as a function of [urea], the molar concentration of urea. The transition curve of each protein was analyzed for ΔG(D)(0), the value of Gibbs free energy change on denaturation (ΔG(D)) in the absence of urea; m, the slope (=∂∆G(D)/∂[urea]), and C(m), the midpoint of the denaturation curve, i.e. [urea] at which ΔG(D) = 0. A difference of about 10% in ΔG(D)(0) observed between FL-αC-PE and Tr-αC-PE, suggests that the two proteins are almost equally stable, and the natural deletion of 31 residues from the N-terminal side of the full length protein does not alter its stability. Furthermore, normalization of probes shows that the urea-induced denaturation of both the proteins is a two-state process. Folding of both structural variants (Tr-αC-PE and FL-αC-PE) of P. tenue were also studied using molecular dynamics simulations at 300 K. The results show clearly that the stability of the proteins is evenly distributed over the whole structure indicating no significant role of N-terminal residues in the stability of both proteins.


Teaching of occupational medicine to undergraduates in UK schools of medicine.
To assess any recent change in the commitment to occupational medicine teaching in UK undergraduate medical curricula. A questionnaire survey of the teaching of occupational medicine to undergraduates in all medical schools listed in the UK Universities and Colleges Admissions Service prospectus for 1999-2000 (n = 24). Nineteen UK schools medical schools returned a completed questionnaire, giving a response rate of 79%. A comparison of results from this survey with previous surveys of teaching of occupational medicine to undergraduates in the UK shows that fewer schools now provide lectures, project work or ward-based tuition in the subject. Workplace visits were not undertaken by any institution. Only two of the schools setting an examination question also had a syllabus. Despite the prominence given to issues related to occupational health in recent UK government policy, this study suggests a declining commitment to occupational medicine on the part of UK medical schools. Urgent action needs to be taken to address the lack of training in occupational medicine in UK medical schools.


A new giant pterosaur with a robust skull from the latest cretaceous of Romania.
A new giant pterosaur, Hatzegopteryx thambema, nov.gen., nov.sp., from the Maastrichtian Densuş-Ciula Formation of Romania is remarkable for its very large size (estimated wing span > or = 12 m) and for the robustness of its large skull, which may have been nearly 3 m long. The stout skull bones contrast with the usually thin and slender skull elements of other pterosaurs, and raise the question of how the weight of the skull was reduced in order to make flight possible. The answer probably lies in the very peculiar internal structure of the bones, which consists of a dense network of very thin trabeculae enclosing small alveoli. This structure is reminiscent of expanded polystyrene and, like it, probably combined strength with lightness.


Race/ethnicity and potential suicide misclassification: window on a minority suicide paradox?
Suicide officially kills approximately 30,000 annually in the United States. Analysis of this leading public health problem is complicated by undercounting. Despite persisting socioeconomic and health disparities, non-Hispanic Blacks and Hispanics register suicide rates less than half that of non-Hispanic Whites. This cross-sectional study uses multiple cause-of-death data from the US National Center for Health Statistics to assess whether race/ethnicity, psychiatric comorbidity documentation, and other decedent characteristics were associated with differential potential for suicide misclassification. Subjects were 105,946 White, Black, and Hispanic residents aged 15 years and older, dying in the US between 2003 and 2005, whose manner of death was recorded as suicide or injury of undetermined intent. The main outcome measure was the relative odds of potential suicide misclassification, a binary measure of manner of death: injury of undetermined intent (includes misclassified suicides) versus suicide. Blacks (adjusted odds ratio [AOR], 2.38; 95% confidence interval [CI], 2.22-2.57) and Hispanics (1.17, 1.07-1.28) manifested excess potential suicide misclassification relative to Whites. Decedents aged 35-54 (AOR, 0.88; 95% CI, 0.84-0.93), 55-74 (0.52, 0.49-0.57), and 75+ years (0.51, 0.46-0.57) showed diminished misclassification potential relative to decedents aged 15-34, while decedents with 0-8 years (1.82, 1.75-1.90) and 9-12 years of education (1.43, 1.40-1.46) showed excess potential relative to the most educated (13+ years). Excess potential suicide misclassification was also apparent for decedents without (AOR, 3.12; 95% CI, 2.78-3.51) versus those with psychiatric comorbidity documented on their death certificates, and for decedents whose mode of injury was "less active" (46.33; 43.32-49.55) versus "more active." Data disparities might explain much of the Black-White suicide rate gap, if not the Hispanic-White gap. Ameliorative action would extend from training in death certification to routine use of psychological autopsies in equivocal-manner-of-death cases.


Defining variant-resistant epitopes targeted by SARS-CoV-2 antibodies: A global consortium study.
Antibody-based therapeutics and vaccines are essential to combat COVID-19 morbidity and mortality after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple mutations in SARS-CoV-2 that could impair antibody defenses propagated in human-to-human transmission and spillover or spillback events between humans and animals. To develop prevention and therapeutic strategies, we formed an international consortium to map the epitope landscape on the SARS-CoV-2 spike protein, defining and structurally illustrating seven receptor binding domain (RBD)–directed antibody communities with distinct footprints and competition profiles. Pseudovirion-based neutralization assays reveal spike mutations, individually and clustered together in variants, that affect antibody function among the communities. Key classes of RBD-targeted antibodies maintain neutralization activity against these emerging SARS-CoV-2 variants. These results provide a framework for selecting antibody treatment cocktails and understanding how viral variants might affect antibody therapeutic efficacy.


Is the chronic fatigue syndrome an exercise phobia? A case control study.
The aim of this study was to test whether patients with chronic fatigue syndrome (CFS) have an exercise phobia, by measuring anxiety-related physiological and psychological reactions to ordinary activity and exercise. Patients and healthy but sedentary controls were assessed over 8 h of an ordinary day, and before, during and after an incremental exercise test on a motorised treadmill. To avoid confounding effects, those with a comorbid psychiatric disorder were excluded. Heart rate, galvanic skin resistance (GSR) and the amount of activity undertaken were measured, along with state and trait measures of anxiety. Patients with CFS were more fatigued and sleep disturbed than were the controls and noted greater effort during the exercise test. No statistically significant differences were found in either heart rate or GSR both during a normal day and before, during and after the exercise test. Patients with CFS were more symptomatically anxious at all times, but this did not increase with exercise. The data suggest that CFS patients without a comorbid psychiatric disorder do not have an exercise phobia.


[The development and effectiveness of telecare from an integrated technological, humanistic and management perspective].
A decreasing birthrate coupled with a growing elderly population has lead to an increased focus on elderly-centric issues such as long-term care and senior healthcare. Recent advances in information, communication and biomedical technologies have combined to allow the development of various types of telemedicine technology designed to enhance or expand patient services and care. To date, most telecare studies have focused on the development of underlying technologies rather than on patient (customer) perceptions regarding service mechanisms. The lack of the latter makes obtaining an effective understanding of the actual needs and problems of the elderly population difficult, and limits the potential for clinical implementation of study findings and further knowledge development. This article reviews important articles in the literature on telecare and evaluates the effectiveness of telecare-related technologies. Three key aspects associated with eight sub-indictors were identified. These included the aspects of technology (system quality); humanism (institutional trust and privacy risk); and management (service quality, cost benefit, satisfaction, use intention, and influence on health). An integrated perspective combining social and technological aspects is needed to facilitate increasing utilization of and satisfaction with telecare. Simply implementing new systems built around this innovative technology is not sufficient, and may be counterproductive. This article was written to help stimulate deeper exploration and insights into academic theory and clinical practice in order to help shape and create a better vision of aging in place.


ERP correlates of target-distracter differentiation in repeated runs of a continuous recognition task with emotional and neutral faces.
The emotional salience of faces has previously been shown to induce memory distortions in recognition memory tasks. This event-related potential (ERP) study used repeated runs of a continuous recognition task with emotional and neutral faces to investigate emotion-induced memory distortions. In the second and third runs, participants made more false alarms to distracters (repeated from previous runs). Emotion did not modulate the amount of errors, but the extent to which recollection was employed to maximise performance as reflected in the putative ERP correlate of recollection; the parietal old-new effect. Targets from all stimulus classes (positive, negative, neutral) were associated with parietal ERP memory effects, but this was also the case for correctly rejected negative distracters. This suggests that recollection was strategically used to correctly reject negative distracters (recall-to-reject). This finding is consistent with the view that facilitated recollection of negative stimuli may be used to decrease the susceptibility to memory errors induced by emotional salience.


Photoexcited Ag ejection from a low-temperature He cluster: a simulation study by nonadiabatic Ehrenfest ring-polymer molecular dynamics.
Ring-polymer molecular dynamics (RPMD) simulations have been performed to understand the photoexcitation dynamics of an Ag atom embedded in a low-temperature cluster consisting of 500 helium atoms, after the electronic excitation 5p 2P1/2 ← 5p 2S1/2 and 5p 2P3/2 ← 5p 2S1/2 of the Ag atom. Along the RPMD trajectory the time evolution of electronic wavefunction within the spin-orbit 2P manifold is calculated, whereby the time-dependent Schrödinger equation and the RPMD equation of motion are coupled, using the à la Ehrenfest mean field approach. It is found from the simulations that the Ag atom is ejected from the helium cluster with the average time of 100 ps after photoexcitation with the average ejection velocity being 60-70 m s-1, which is roughly in line with experiment. Meanwhile it is also found that the present simulations do not agree with experiment as to the final state of the ejected Ag atom.


Blood pressure control, microalbuminuria and cardiovascular risk in Type 2 diabetes mellitus.
Type 2 (noninsulin-dependent) diabetes mellitus (DM) affects about 3% of the UK population. Diabetes often coexists with a cluster of other potent cardiovascular risk factors, including hypertension, dyslipidaemia and increased tendency for thrombosis, and increases the risk of early death from cardiovascular causes by about threefold. Microalbuminuria or proteinuria also may be present, further increasing the risk of cardiovascular mortality. Cardiovascular risk factors must be treated aggressively in patients with Type 2 diabetes and control of blood pressure at 140/85 mm Hg or lower is a priority. The management of hypertension in patients from some ethnic groups demands special consideration because they have a high incidence of diabetes and hypertensive complications. Patients must be urged to adopt appropriate lifestyle changes in the first instance but additional drug treatment for hypertension is usually required. All the major classes of antihypertensive agents lower blood pressure in Type 2 diabetic patients but have different effects on metabolic risk factors in different ways. Low-dose thiazide diuretics, beta-blockers, calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors have been shown to reduce cardiovascular risk. Individually, the effects of low-dose thiazide diuretics and beta-blockers on glucose and lipid metabolism is clinically insignificant, though in combination much larger metabolic effects are seen. ACE inhibitors and calcium channel blockers have no, or small, beneficial effects on glucose and lipid metabolism, while the greater beneficial effects of alpha1-blockers on lipid profiles may render them especially useful in the Type 2 diabetic patient. Long-acting calcium-channel blockers and ACE inhibitors protect renal function and are suitable as first line therapy in patients with microalbuminuria or proteinuria. Until results from the current batch of randomized, placebo-controlled trials comparing different classes of antihypertensive agents are available, the choice of antihypertensive agent is difficult. Addressing overall cardiovascular risk factors, rather than hypertension alone, is essential in the management of the hypertensive Type 2 diabetic patient.


Knee manipulation under anaesthetic following total knee arthroplasty: a matched cohort design.
The purpose of this study was to compare clinical outcomes of total knee arthroplasty (TKA) after manipulation under anaesthesia (MUA) for post-operative stiffness with a matched cohort of TKA patients who did not requre MUA. In total 72 patients (mean age 59.8 years, 42 to 83) who underwent MUA following TKA were identified from our prospective database and compared with a matched cohort of patients who had undergone TKA without subsequent MUA. Patients were evaluated for range of movement (ROM) and clinical outcome scores (Western Ontario and McMaster Universities Arthritis Index, Short-Form Health Survey, and Knee Society Clinical Rating System) at a mean follow-up of 36.4 months (12 to 120). MUA took place at a mean of nine weeks (5 to 18) after TKA. In patients who required MUA, mean flexion deformity improved from 10° (0° to 25°) to 4.4° (0° to 15°) (p < 0.001), and mean range of flexion improved from 79.8° (65° to 95°) to 116° (80° to 130°) (p < 0.001). There were no statistically significant differences in ROM or functional outcome scores at three months, one year, or two years between those who required MUA and those who did not. There were no complications associated with manipulation. At most recent follow-up, patients requiring MUA achieved equivalent ROM and clinical outcome scores when compared with a matched control group. While other studies have focused on ROM after manipulation, the current study adds to current literature by supplementing this with functional outcome scores.


Effects of serotonin antagonists on blood pressure in mineralocorticoid hypertensive sheep.
The serotonin antagonist methysergide has a partial agonistic action on isolated vascular smooth muscle from hypertensive animals, whereas ketanserin, another serotonin antagonist, does not. The goal of this study was to determine the effects of these two agents on blood pressure in the conscious, deoxycorticosterone acetate (DOCA) hypertensive sheep. Adult sheep maintained on a standard laboratory diet and 0.1% NaCl/0.25% KCl drinking water developed hypertension following DOCA implantation (mean arterial pressure: control = 83 mm Hg, DOCA = 108 mm Hg). Methysergide (40 micrograms/kg--i.v. bolus) produced a greater pressor response in hypertensive sheep than in normotensive sheep (control = 8 +/- 1 mm Hg, DOCA = 18 +/- 3 mm Hg). Ketanserin (50 micrograms/kg--i.v. bolus), on the other hand, caused a similar decrease in blood pressure (approximately -16 mm Hg) in both control and DOCA sheep. Pressor responses to infusions of serotonin were greater in DOCA sheep compared with controls. Both methysergide and ketanserin were equally effective antagonists of a serotonin-induced pressor response (75% inhibition) in control and DOCA sheep. Methysergide had no effect on a norepinephrine-induced pressor response, but ketanserin caused a 20% attenuation of this response. These results demonstrate an enhanced responsiveness to serotonin and methysergide in DOCA hypertensive sheep.


Imputation of systematically missing predictors in an individual participant data meta-analysis: a generalized approach using MICE.
Individual participant data meta-analyses (IPD-MA) are increasingly used for developing and validating multivariable (diagnostic or prognostic) risk prediction models. Unfortunately, some predictors or even outcomes may not have been measured in each study and are thus systematically missing in some individual studies of the IPD-MA. As a consequence, it is no longer possible to evaluate between-study heterogeneity and to estimate study-specific predictor effects, or to include all individual studies, which severely hampers the development and validation of prediction models. Here, we describe a novel approach for imputing systematically missing data and adopt a generalized linear mixed model to allow for between-study heterogeneity. This approach can be viewed as an extension of Resche-Rigon's method (Stat Med 2013), relaxing their assumptions regarding variance components and allowing imputation of linear and nonlinear predictors. We illustrate our approach using a case study with IPD-MA of 13 studies to develop and validate a diagnostic prediction model for the presence of deep venous thrombosis. We compare the results after applying four methods for dealing with systematically missing predictors in one or more individual studies: complete case analysis where studies with systematically missing predictors are removed, traditional multiple imputation ignoring heterogeneity across studies, stratified multiple imputation accounting for heterogeneity in predictor prevalence, and multilevel multiple imputation (MLMI) fully accounting for between-study heterogeneity. We conclude that MLMI may substantially improve the estimation of between-study heterogeneity parameters and allow for imputation of systematically missing predictors in IPD-MA aimed at the development and validation of prediction models.


Impact of Pretransplantation (18)F-fluorodeoxy Glucose-Positron Emission Tomography Status on Outcomes after Allogeneic Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma.
Assessment with (18)F-fluorodeoxy glucose (FDG)-positron emission tomography (PET) before hematopoietic cell transplantation (HCT) for lymphoma may be prognostic for outcomes. Patients with chemotherapy-sensitive non-Hodgkin lymphoma (NHL) undergoing allogeneic HCT reported to the Center of International Blood and Marrow Transplantation Registry between 2007 and 2012 were included. Pre-HCT PET status (positive versus negative) was determined by the reporting transplantation centers. We analyzed 336 patients; median age was 55 years and 60% were males. Follicular lymphoma (n = 104) was more common than large cell (n = 85), mantle cell (n = 69), and mature natural killer or T cell lymphoma (n = 78); two thirds of the cohort received reduced-intensity conditioning; one half had unrelated donor grafts. Patients underwent PET scanning a median of 1 month (range, .07 to 2.83 months) before HCT; 159 were PET positive and 177 were PET negative. At 3 years, relapse/progression, progression-free survival (PFS), and overall survival (OS) in PET-positive versus PET-negative groups were 40% versus 26%; P = .007; 43% versus 47%; P = .47; and 58% versus 60%; P = .73, respectively. On multivariate analysis, a positive pretransplantation PET was associated with an increased risk of relapse/progression (risk ratio [RR], 1.86; P = .001) but was not associated with increased mortality (RR, 1.29, 95% confidence interval [CI], .96 to 1.7; P = .08), therapy failure (RR, 1.32; 95% CI, .95 to 1.84; P = .10), or nonrelapse mortality (RR, .75; 95% CI, .48 to 1.18; P = .22). PET status conferred no influence on graft-versus-host disease. A positive PET scan before HCT is associated with increased relapse risk but should not be interpreted as a barrier to a successful allograft. PET status does not appear to predict survival after allogeneic HCT for NHL.


Unpacking the 'black box' of total pathogen burden: is number or type of pathogens most predictive of all-cause mortality in the United States?
A 'black box' paradigm has prevailed in which researchers have focused on the association between the total number of pathogens for which individuals are seropositive (i.e. total pathogen burden) and various chronic diseases, while largely ignoring the role that seropositivity for specific combinations of pathogens may play in the aetiology of such outcomes and consequently mortality. We examined the association between total pathogen burden as well as specific pathogen combinations and all-cause mortality in the United States. Data were from individuals aged ⩾25 years tested for cytomegalovirus (CMV), herpes simplex virus (HSV)-1, HSV-2 and Helicobacter pylori, with mortality follow-up to 31 December 2006 in the National Health and Nutrition Examination Survey (NHANES) III (N = 6522). We did not observe a statistically significant graded relationship between total pathogen burden level and all-cause mortality. Furthermore, compared to those seronegative for all four pathogens, the greatest statistically significant rate of all-cause mortality was for those CMV+/HSV-2+ (hazard ratio 1·95, 95% confidence interval 1·13-3·35) adjusting for age, gender, race/ethnicity, education level, body mass index (kg/m2) and smoking status. Interventions targeting prevention or treatment of particular pathogens may be more effective for reducing mortality than those focused solely on reducing overall pathogen burden.


Selective autophagy degrades DICER and AGO2 and regulates miRNA activity.
MicroRNAs (miRNAs) form a class of short RNAs (∼ 21 nucleotides) that post-transcriptionally regulate partially complementary messenger RNAs. Each miRNA may target tens to hundreds of transcripts to control key biological processes. Although the biochemical reactions underpinning miRNA biogenesis and activity are relatively well defined and the importance of their homeostasis is increasingly evident, the processes underlying regulation of the miRNA pathway in vivo are still largely elusive. Autophagy, a degradative process in which cytoplasmic material is targeted into double-membrane vacuoles, is recognized to critically contribute to cellular homeostasis. Here, we show that the miRNA-processing enzyme, DICER (also known as DICER1), and the main miRNA effector, AGO2 (also known as eukaryotic translation initiation factor 2C, 2 (EIF2C2)), are targeted for degradation as miRNA-free entities by the selective autophagy receptor NDP52 (also known as calcium binding and coiled-coil domain 2 (CALCOCO2)). Autophagy establishes a checkpoint required for continued loading of miRNA into AGO2; accordingly, NDP52 and autophagy are required for homeostasis and activity of the tested miRNAs. Autophagy also engages post-transcriptional regulation of the DICER mRNA, underscoring the importance of fine-tuned regulation of the miRNA pathway. These findings have implications for human diseases linked to misregulated autophagy, DICER- and miRNA-levels, including cancer.


Limited genetic parallelism underlies recent, repeated incipient speciation in geographically proximate populations of an Arctic fish (Salvelinus alpinus).
The genetic underpinnings of incipient speciation, including the genomic mechanisms which contribute to morphological and ecological differentiation and reproductive isolation, remain poorly understood. The repeated evolution of consistently, phenotypically distinct morphs of Arctic Charr (Salvelinus alpinus) within the Quaternary period offer an ideal model to study the repeatability of evolution at the genomic level. Sympatric morphs of Arctic Charr are found across this species' circumpolar distribution. However, the specific genetic mechanisms driving this morph differentiation are largely unknown despite the cultural and economic importance of the anadromous morph. We used a newly designed 87k SNP chip to investigate the character and consistency of the genomic differences among sympatric morphs within three recently deglaciated and geographically proximate lakes in Labrador, Canada. We found genetically distinct small and large morph Arctic Charr in all three lakes consistent with resident and anadromous morphs, respectively. A degree of reproductive isolation among sympatric morphs is likely given genome-wide distributions of outlier SNPs and high genome-wide FST s. Across all lakes, outlier SNPs were largely nonoverlapping suggesting a lack of genetic parallelism driving morph differentiation. Alternatively, several genes and paralogous copies of the same gene consistently differentiated morphs across multiple lakes suggesting their importance to the manifestation of morphs. Our results confirm the utility of Arctic Charr as a model for investigating the predictability of evolution and support the importance of both genetic parallelism and nonparallelism to the incipient speciation of Arctic Charr morphs.


NSP-Dependent Simple Nitrile Formation Dominates upon Breakdown of Major Aliphatic Glucosinolates in Roots, Seeds, and Seedlings of Arabidopsis thaliana Columbia-0.
One of the best-studied plant defense systems, the glucosinolate-myrosinase system of the Brassicales, is composed of thioglucosides known as glucosinolates and their hydrolytic enzymes, the myrosinases. Tissue disruption brings these components together, and bioactive products are formed as a consequence of myrosinase-catalyzed glucosinolate hydrolysis. Among these products, isothiocyanates have attracted most interest as chemical plant defenses against herbivores and pathogens and health-promoting compounds in the human diet. Previous research has identified specifier proteins whose presence results in the formation of alternative product types, e.g., nitriles, at the expense of isothiocyanates. The biological roles of specifier proteins and alternative breakdown products are poorly understood. Here, we assessed glucosinolate breakdown product profiles obtained upon maceration of roots, seedlings and seeds of Arabidopsis thaliana Columbia-0. We identified simple nitriles as the predominant breakdown products of the major endogenous aliphatic glucosinolates in root, seed, and seedling homogenates. In agreement with this finding, genes encoding nitrile-specifier proteins (NSPs) are expressed in roots, seeds, and seedlings. Analysis of glucosinolate breakdown in mutants with T-DNA insertions in any of the five NSP genes demonstrated, that simple nitrile formation upon tissue disruption depended almost entirely on NSP2 in seeds and mainly on NSP1 in seedlings. In roots, about 70-80% of the nitrile-forming activity was due to NSP1 and NSP3. Thus, glucosinolate breakdown product profiles are organ-specifically regulated in A. thaliana Col-0, and high proportions of simple nitriles are formed in some parts of the plant. This should be considered in future studies on biological roles of the glucosinolate-myrosinase system.


The effects of a progressive resistance training program on walking ability in patients after stroke: a pilot study.
[Purpose] The purpose of this study was to evaluate the effects of a progressive resistance training (PRT) program on the walking ability of chronic stroke patients with hemiparesis following chronic stroke. [Subjects and Methods] The participants of this study were fifteen hemiplegic patients. The main outcomes measured for this study were the peak torque of the knee extensor; the gait ability as measured by electric gait analysis of walking speed, walking cycle, affected side stance phase, affected side stride length, symmetry index of stance phase, and symmetry index of stride length; and 10-m walking speed; and the Berg balance scale test. [Results] Walking speed and affected side stride length significantly increased after the PRT program, and 10-m walking time significantly decreased after RPT in stroke patients. [Conclusion] These results suggest that the progressive resistance training program may, in part, improve the stride of the affected side leg of stroke patients after stroke and also positively impact walking speed.


Adaptations in nucleus accumbens circuitry during opioid withdrawal associated with persistence of noxious stimulus-induced antinociception in the rat.
We studied adaptations in nucleus accumbens opioidergic circuitry mediating noxious stimulus-induced antinociception (NSIA) in rats withdrawing from chronic morphine administration. Although the magnitude of NSIA in withdrawing rats was similar to that observed in naïve rats despite the tolerance of withdrawing rats to the antinociceptive effects of acutely administered morphine, the involvement of nucleus accumbens opioid receptors in NSIA in withdrawing rats was different from previous observations in both naïve and tolerant rats. In withdrawing rats intra-accumbens administration of the mu-opioid receptor antagonist Cys2, Tyr3, Orn5, Pen7 amide (CTOP), but not the delta-receptor antagonist naltrindole, blocked NSIA. Both antagonists blocked NSIA in the naïve state, but neither was effective in tolerant rats. Also, intra-accumbens administration of the mu-agonist [D-Ala2, N-Me-Phe(4,) Gly5-ol]-enkephalin (DAMGO) alone was sufficient to induce antinociception in withdrawing rats, whereas a combination of both mu- and delta-receptor agonists (ie, DAMGO and D-Pen(2,5)-enkephalin [DPDPE], respectively) is required to induce antinociception in naïve rats. The delta- agonist DPDPE was without effect in the withdrawing rat, alone or when combined with DAMGO. Thus, although the magnitude of NSIA does not differ significantly among the 3 states, it is mediated by both mu- and delta-receptors in the naive rat, mu- but not delta-receptors in the withdrawing rat, and neither receptor type in the morphine tolerant rat. These changes may result from different degrees of tolerance, with delta-receptors being the most sensitive; however, it is not known how these changes occur without affecting the magnitude of the resultant antinociception.


Exothermicity Is Not a Necessary Condition for Enhanced Diffusion of Enzymes.
Recent experiments have revealed that the diffusivity of exothermic and fast enzymes is enhanced when they are catalytically active, and different physical mechanisms have been explored and quantified to account for this observation. We perform measurements on the endothermic and relatively slow enzyme aldolase, which also shows substrate-induced enhanced diffusion. We propose a new physical paradigm, which reveals that the diffusion coefficient of a model enzyme hydrodynamically coupled to its environment increases significantly when undergoing changes in conformational fluctuations in a substrate concentration dependent manner, and is independent of the overall turnover rate of the underlying enzymatic reaction. Our results show that substrate-induced enhanced diffusion of enzyme molecules can be explained within an equilibrium picture and that the exothermicity of the catalyzed reaction is not a necessary condition for the observation of this phenomenon.


Vocal babbling in a wild parrot shows life history and endocrine affinities with human infants.
Prelinguistic babbling is a critical phase in infant language development and is best understood in temperate songbirds where it occurs primarily in males at reproductive maturity and is modulated by sex steroids. Parrots of both sexes are icons of tropical vocal plasticity, but vocal babbling is unreported in this group and whether the endocrine system is involved is unknown. Here we show that vocal babbling is widespread in a wild parrot population in Venezuela, ensues in both sexes during the nestling stage, occurs amidst a captive audience of mixed-aged siblings, and is modulated by corticosteroids. Spectrographic analysis and machine learning found phoneme diversity and combinatorial capacity increased precipitously for the first week, thereafter, crystalizing into a smaller repertoire, consistent with the selective attrition model of language development. Corticosterone-treated nestlings differed from unmanipulated birds and sham controls in several acoustic properties and crystallized a larger repertoire post-treatment. Our findings indicate babbling occurs during an early life-history stage in which corticosteroids help catalyse the transition from a universal learning programme to one finely tuned for the prevailing ecological environment, a potentially convergent scenario in human prelinguistic development.


Environmental restoration of invaded ecosystems: how much versus how often?
This paper derives the optimal level of restorative efforts required to restore environments degraded by invasive species invasion. Specific attention is focused on a case when restoration faces the risk of failure through relapse of the restored environment caused by repeat invasions. The level of restored environment may also play a role in its future improvement or susceptibility to failure. The tradeoff between the optimal level of environmental quality and number of restorative efforts required to attain that given environmental quality is highlighted.


Successful long-term treatment of Cushing disease with mifepristone (RU486).
We describe a girl with Cushing disease for whom surgery and radiation treatments failed and the subsequent clinical course with mifepristone therapy. We present the patient's clinical, biochemical, and imaging findings. A 16-year-old girl presented with classic Cushing disease. After transsphenoidal surgery, Cyberknife radiosurgery, ketoconazole, and metyrapone did not control her disease, and she was prescribed mifepristone, which was titrated to a maximal dosage of 1200 mg daily with subsequent symptom improvement. Mifepristone (RU486) is a high-affinity, nonselective antagonist of the glucocorticoid receptor. There is limited literature on its use as an off-label medication to treat refractory Cushing disease. Over her 8-year treatment with mifepristone, her therapy was complicated by hypertension and hypokalemia requiring spironolactone and potassium chloride. She received a 2-month drug holiday every 4 to 6 months to allow for withdrawal menstrual bleeding with medroxyprogesterone acetate. Urinary cortisol, serum cortisol, and corticotropin levels remained elevated during mifepristone drug holidays. While on mifepristone, her signs and symptoms of Cushing disease resolved. Repeated magnetic resonance imaging demonstrated stable appearance of the residual pituitary mass. Bilateral adrenalectomy was performed, and mifepristone was discontinued after 95 months of medical therapy. We describe the longest duration of mifepristone therapy thus reported for the treatment of refractory Cushing disease. Mifepristone effectively controlled all signs and symptoms of hypercortisolism. Menstruating women who take the drug on a long-term basis should receive periodic drug holidays to allow for menses. The lack of reliable serum biomarkers to monitor the success of mifepristone therapy requires careful clinical judgment and may make its use difficult in Cushing disease.


Promoting coordination in Norwegian health care.
The Norwegian health care system is well organized within its two main sectors-primary health and long-term care on the one hand, and hospitals and specialist services on the other. However, the relation between them lacks mediating structures. Enhancing coordination between primary and secondary health care has been central in Norwegian health care policy in the last decade. In 2003 a committee was appointed to identify coordination problems and proposed a lot of practical and organisational recommendations. It relied on an approach challenging primary and secondary health care in shared geographical regions to take action. However, these proposals were not implemented. In 2008 a new Minister of Health and Care worked out plans under the key term "Coordination Reform". These reform plans superseded and expanded the previous policy initiatives concerning cooperation, but represented also a shift in focus to a regulative and centralised strategy, including new health legislation, structural reforms and use of economic incentives that are now about to be implemented. The article analyses the perspectives and proposals of the previous and the recent reform initiatives in Norway and discusses them in relation to integrated care measures implemented in Denmark and Sweden.