Exploring the adoption of Schwartz Center Rounds as an organisational innovation to improve staff well-being in England, 2009-2015.
Schwartz Center Rounds ('Rounds') are a multidisciplinary forum in which healthcare staff within an organisation discuss the psychological, emotional and social challenges associated with their work in a confidential and safe environment. Implemented in over 375 North American organisations, since 2009, they have been increasingly adopted in England. This study aimed to establish how many and what types of organisations have adopted Rounds in England, and to explore why they did so. Public healthcare organisations in England. Secondary data analysis was used to map and profile all 116 public healthcare organisations that had adopted Rounds in England by July 2015. Semistructured telephone interviews were conducted with 45 Round coordinators within adopting organisations. The rate of adoption increased after a major national report in 2013. Rounds were typically adopted in order to improve staff well-being. Adopting organisations scored better on staff engagement than non-adopters; among adopting organisations, those performing better on patient experience were more likely to adopt earlier. Most adoption decision-making processes were straightforward. A confluence of factors-a generally favourable set of innovation attributes (including low cost), advocacy from opinion leaders in different professional networks, active dissemination by change agents and a felt need to be seen to be addressing staff well-being-initially led to Rounds being seen as 'an idea whose time had come'. More recent adoption patterns have been shaped by the timing of charitable and other agency funding in specific geographical areas and sectors, as well as several forms of 'mimetic pressure'. The innate attributes of Rounds, favourable circumstances and the cumulative impact of a sequence of distinct informal and formal social processes have shaped the pattern of their adoption in England.


The basis of musical consonance as revealed by congenital amusia.
Some combinations of musical notes sound pleasing and are termed "consonant," but others sound unpleasant and are termed "dissonant." The distinction between consonance and dissonance plays a central role in Western music, and its origins have posed one of the oldest and most debated problems in perception. In modern times, dissonance has been widely believed to be the product of "beating": interference between frequency components in the cochlea that has been believed to be more pronounced in dissonant than consonant sounds. However, harmonic frequency relations, a higher-order sound attribute closely related to pitch perception, has also been proposed to account for consonance. To tease apart theories of musical consonance, we tested sound preferences in individuals with congenital amusia, a neurogenetic disorder characterized by abnormal pitch perception. We assessed amusics' preferences for musical chords as well as for the isolated acoustic properties of beating and harmonicity. In contrast to control subjects, amusic listeners showed no preference for consonance, rating the pleasantness of consonant chords no higher than that of dissonant chords. Amusics also failed to exhibit the normally observed preference for harmonic over inharmonic tones, nor could they discriminate such tones from each other. Despite these abnormalities, amusics exhibited normal preferences and discrimination for stimuli with and without beating. This dissociation indicates that, contrary to classic theories, beating is unlikely to underlie consonance. Our results instead suggest the need to integrate harmonicity as a foundation of music preferences, and illustrate how amusia may be used to investigate normal auditory function.


Antigen phagocytosis by B cells is required for a potent humoral response.
Successful vaccines rely on activating a functional humoral response that results from promoting a proper germinal center (GC) reaction. Key in this process is the activation of follicular B cells that need to acquire antigens and to present them to cognate CD4 T cells. Here, we report that follicular B cells can phagocytose large antigen-coated particles, a process thought to be exclusive of specialized antigen-presenting cells such as macrophages and dendritic cells. We show that antigen phagocytosis by B cells is BCR-driven and mechanistically dependent on the GTPase RhoG. Using Rhog-/- mice, we show that phagocytosis of antigen by B cells is important for the development of a strong GC response and the generation of high-affinity class-switched antibodies. Importantly, we show that the potentiation effect of alum, a common vaccine adjuvant, requires direct phagocytosis of alum-antigen complexes by B cells. These data suggest a new avenue for vaccination approaches by aiming to deliver 1-3 μm size antigen particles to follicular B cells.


Implication of the human Binder of SPerm Homolog 1 (BSPH1) protein in capacitation.
Binder of SPerm (BSP) proteins are a family of proteins expressed exclusively in the male reproductive tract (seminal vesicles or epididymis) of several mammalian species. They are known to promote capacitation, a sperm maturation step essential for fertilization. Our recent studies have shown that in human, the Binder of SPerm Homolog 1 (BSPH1) is expressed solely in epididymal tissues. The goal of the current study was to characterize BSPH1 and evaluate its effect on different sperm functions. A human recombinant BSPH1 (rec-BSPH1) was produced, purified and refolded. Rec-BSPH1 was found to share many characteristics with other members of the BSP superfamily, as it was able to bind gelatin and heparin as well as capacitate sperm. Rec-BSPH1 had no effect on sperm acrosome reaction or any sperm motility parameters. Native BSPH1 was localized on the equatorial segment, post-acrosomal segment and neck of ejaculated human sperm. Rec-BSPH1, following incubation with washed ejaculated human sperm, exhibited binding patterns similar to the native protein. These results show that the human epididymal BSPH1 shares many biochemical and functional characteristics with BSP proteins secreted by seminal vesicles of ungulates, and behaves similarly to its murine epididymal orthologue BSPH1. This study of human BSPH1 brings us one step closer to understanding the importance of this protein in male fertility.


Icodextrin use for peritoneal dialysis in Australia: A cohort study using Australia and New Zealand Dialysis and Transplant Registry.
Icodextrin is a high molecular weight, starch-derived glucose polymer that is used as an osmotic agent in peritoneal dialysis (PD) to promote ultrafiltration. There has been wide variation in its use across Australia and the rest of the world, but it is unclear whether these differences are due to patient- or centre-related factors. Using the Australia and New Zealand Dialysis and Transplant Registry, all adult patients (>18 years) who started PD in Australia between 1 January 2007 and 31 December 2014 were included. The primary outcome was icodextrin use at PD commencement. Hierarchical logistic regression clustered around the treatment centre was applied to determine the patient- and centre-related characteristics associated with icodextrin use. The impact of centre-level practice pattern variability on icodextrin uptake was estimated using the intra-cluster correlation coefficient (ICC). Of 5948 patients starting on PD in 58 centres during the study period, 2002 (33.7%) received icodextrin from the outset. Overall uptake of icodextrin increased from 29% in 2010 to 42.5% in 2014. Patient-level characteristics associated with an increased likelihood of commencing PD with icodextrin included male sex (adjusted odds ratio (OR) 1.55, 95% confidence interval (CI) 1.35-1.77; p < 0.001), prior haemodialysis or kidney transplantation (OR 1.26, 95% CI 1.09-1.47), obesity (OR 1.66, 95% CI 1.41-1.96), diabetes mellitus (OR 2.32, 95% CI 2.03-2.64) and residing in a postcode with the highest decile of socio-economic status (OR 1.43, 95% CI 1.11-1.85). The centre-level characteristic associated with an increased likelihood of commencing PD with icodextrin was routine assessment of a peritoneal equilibration test (OR 1.45, 95% CI 1.27-1.66). Centres with fewer patients on automated peritoneal dialysis (APD) were less likely to start on icodextrin (APD proportion <57%; OR 0.45, 95% CI 0.20-0.99). Centre factors accounted for 25% of the variation in icodextrin use solution among incident PD patients (ICC 0.25). Icodextrin use in incident Australian PD patients is increasing variable and associated with both patient and centre characteristics. Centre-related factors explained 25% of variability in icodextrin use.


Pre-T Cell Receptors (Pre-TCRs) Leverage Vβ Complementarity Determining Regions (CDRs) and Hydrophobic Patch in Mechanosensing Thymic Self-ligands.
The pre-T cell receptor (pre-TCR) is a pTα-β heterodimer functioning in early αβ T cell development. Although once thought to be ligand-autonomous, recent studies show that pre-TCRs participate in thymic repertoire formation through recognition of peptides bound to major histocompatibility molecules (pMHC). Using optical tweezers, we probe pre-TCR bonding with pMHC at the single molecule level. Like the αβTCR, the pre-TCR is a mechanosensor undergoing force-based structural transitions that dynamically enhance bond lifetimes and exploiting allosteric control regulated via the Cβ FG loop region. The pre-TCR structural transitions exhibit greater reversibility than TCRαβ and ordered force-bond lifetime curves. Higher piconewton force requires binding through both complementarity determining region loops and hydrophobic Vβ patch apposition. This patch functions in the pre-TCR as a surrogate Vα domain, fostering ligand promiscuity to favor development of β chains with self-reactivity but is occluded by α subunit replacement of pTα upon αβTCR formation. At the double negative 3 thymocyte stage where the pre-TCR is first expressed, pre-TCR interaction with self-pMHC ligands imparts growth and survival advantages as revealed in thymic stromal cultures, imprinting fundamental self-reactivity in the T cell repertoire. Collectively, our data imply the existence of sequential mechanosensor αβTCR repertoire tuning via the pre-TCR.


Multiple binding modes of a moderate ice-binding protein from a polar microalga.
Ice-binding proteins (IBPs) produced by cold-tolerant organisms interact with ice and strongly control crystal growth. The molecular basis for the different magnitudes of activity displayed by various IBPs (moderate and hyperactive) has not yet been clarified. Previous studies questioned whether the moderate activity of some IBPs relies on their weaker binding modus to the ice surface, compared to hyperactive IBPs, rather than relying on binding only to selected faces of the ice crystal. We present the structure of one moderate IBP from the sea-ice diatom Fragilariopsis cylindrus (fcIBP) as determined by X-ray crystallography and investigate the protein's binding modes to the growing ice-water interface using molecular dynamics simulations. The structure of fcIBP is the IBP-1 fold, defined by a discontinuous β-solenoid delimitated by three faces (A, B and C-faces) and braced by an α-helix. The fcIBP structure shows capping loops on both N- and C-terminal parts of the solenoid. We show that the protein adsorbs on both the prism and the basal faces of ice crystals, confirming experimental results. The fcIBP binds irreversibly to the prism face using the loop between the B and the C-faces, involving also the B-face in water immobilization despite its irregular structure. The α-helix attaches the protein to the basal face with a partly reversible modus. Our results suggest that fcIBP has a looser attachment to ice and that this weaker binding modus is the basis to explain the moderate activity of fcIBP.


Human monoclonal antibodies that inhibit binding of hepatitis C virus E2 protein to CD81 and recognize conserved conformational epitopes.
The intrinsic variability of hepatitis C virus (HCV) envelope proteins E1 and E2 complicates the identification of protective antibodies. In an attempt to identify antibodies to E2 proteins from divergent HCV isolates, we produced HCV E2 recombinant proteins from individuals infected with HCV genotypes 1a, 1b, 2a, and 2b. These proteins were then used to characterize 10 human monoclonal antibodies (HMAbs) produced from peripheral B cells isolated from an individual infected with HCV genotype 1b. Nine of the antibodies recognize conformational epitopes within HCV E2. Six HMAbs identify epitopes shared among HCV genotypes 1a, 1b, 2a, and 2b. Six, including five broadly reactive HMAbs, could inhibit binding of HCV E2 of genotypes 1a, 1b, 2a, and 2b to human CD81 when E2 and the antibody were simultaneously exposed to CD81. Surprisingly, all of the antibodies that inhibited the binding of E2 to CD81 retained the ability to recognize preformed CD81-E2 complexes generated with some of the same recombinant E2 proteins. Two antibodies that did not recognize preformed complexes of HCV 1a E2 and CD81 also inhibited binding of HCV 1a virions to CD81. Thus, HCV-infected individuals can produce antibodies that recognize conserved conformational epitopes and inhibit the binding of HCV to CD81. The inhibition is mediated via antibody binding to epitopes outside of the CD81 binding site in E2, possibly by preventing conformational changes in E2 that are required for CD81 binding.


Ultrahigh Energy Storage Density in Glassy Ferroelectric Thin Films under Low Electric Field.
The current approach to achieving superior energy storage density in dielectrics is to increase their breakdown strength, which often incurs heat generation and unexpected insulation failures, greatly deteriorating the stability and lifetime of devices. Here, a strategy is proposed for enhancing recoverable energy storage density (Wr ) while maintaining a high energy storage efficiency (η) in glassy ferroelectrics by creating super tetragonal (super-T) nanostructures around morphotropic phase boundary (MPB) rather than exploiting the intensely strong electric fields. Accordingly, a giant Wr of ≈86 J cm-3 concomitant with a high η of ≈81% is acquired under a moderate electric field (1.7 MV cm-1 ) in thin films having MPB composition, namely, 0.94(Bi, Na)TiO3 -0.06BaTiO3 (BNBT), where the local super-T polar clusters (tetragonality ≈1.25) are stabilized by interphase strain. To the knowledge of the authors, the Wr of the engineered BNBT thin films represents a new record among all the oxide perovskites under a similar strength of electric field to date. The phase field simulation results ascertain that the improved Wr is attributed to the local strain heterogeneity and the large spontaneous polarization primarily is originated from the super-T polar clusters. The findings in this work present a genuine opportunity to develop ultrahigh-energy-density thin-film capacitors for low-electric-field-driven nano/microelectronics.


Use of adenosine to identify patients at risk for recurrence of accessory pathway conduction after initially successful radiofrequency catheter ablation.
The use of adenosine after radiofrequency catheter ablation of accessory pathways was prospectively studied to determine its utility for identifying patients at risk for recurrence of accessory pathway conduction and to guide therapy that might reduce late recurrence in this group. Accessory pathway conduction recurs in 5%-12% of patients following initially "successful" radiofrequency catheter ablation. Adenosine may facilitate conduction over accessory pathways that have been modified by radiofrequency delivery, thus identifying patients at risk for recurrence. Radiofrequency catheter ablation was performed in 109 patients. Prior to ablation, 12-18 mg of adenosine was administered. After ablation, when all evidence of accessory pathway conduction remained absent for at least 30 minutes, adenosine 12-18 mg was again administered. Adenosine given prior to radiofrequency catheter ablation did not block accessory pathway conduction in any patient. Adenosine given after elimination of accessory pathway conduction induced complete atrioventricular and ventriculoatrial block in 95 patients; 11 (11.6%) subsequently had recurrence of accessory pathway function. Accessory pathway conduction was unmasked by adenosine in 12 patients (11.2%). After further deliveries of radiofrequency energy, 7 of these 12 patients subsequently demonstrated adenosine induced atrioventricular and ventriculoatrial block; 1 of these 7 patients experienced recurrence of accessory pathway conduction. The remaining 5 patients demonstrated persistent accessory pathway conduction only with adenosine; all experienced clinical recurrence of accessory pathway function. The use of adenosine after presumed successful radiofrequency catheter ablation may reveal persistent accessory pathway conduction. Elimination of this latent accessory pathway conduction reduces the risk for recurrence.


[Recurrent episodes of brushite nephrolithiasis revealing primary hyperparathyroidism].
Nephrolithiasis is a frequent disease observed in 1 to 20 % of the general population. This disease predominates in male patients (2:1) and is characterized by a high rate of recurrences (about 50 %). We report the case of a 45-year old male patient who experienced during about ten years recurrent bilateral renal colic episodes due to brushite lithiasis. These stones were treated with multiple extracorporeal shock wave lithotripsy sessions. A pyeloureteral junction syndrome predisposing to bulky stones formation has been put in evidence and required a pyeloplasty. After more than ten years of disease activity, a biochemical screening diagnosed primary hyperparathyroidism (PHPT). Radiological assessment identified a parathyroid gland adenoma. Successful surgical removal of this lesion was followed by resolution of the symptomatic kidney stones formation. PHPT is associated with kidney stones in about 20 % of the patients. Hypercalciuria is the main risk factor of stones formation but other predisposing factors are also probably involved. Patients carrying a polymorphism located in the coding sequence of the calcium-sensing receptor gene or in the regulatory region of this gene seem to experience an increased occurrence of urinary lithiasis. The present case stresses the importance of a metabolic assessment in all patients with recurrent nephrolithiasis, especially in case of bilateral episodes.


Therapeutic Treatment of Arthritic Mice with 15-Deoxy Δ12,14-Prostaglandin J2 (15d-PGJ2) Ameliorates Disease through the Suppression of Th17 Cells and the Induction of CD4+CD25-FOXP3+ Cells.
The prostaglandin, 15-deoxy Δ12,14-prostaglandin J2 (15d-PGJ2), is a lipid mediator that plays an important role in the control of chronic inflammatory disease. However, the role of prostanoid in rheumatoid arthritis (RA) is not well determined. We demonstrated the therapeutic effect of 15d-PGJ2 in an experimental model of arthritis. Daily administration of 15d-PGJ2 attenuated the severity of CIA, reducing the clinical score, pain, and edema. 15d-PGJ2 treatment was associated with a marked reduction in joint levels of proinflammatory cytokines. Although the mRNA expression of ROR-γt was profoundly reduced, FOXP3 was enhanced in draining lymph node cells from 15d-PGJ2-treated arthritic mice. The specific and polyclonal CD4+ Th17 cell responses were limited during the addition of prostaglandin to cell culture. Moreover, in vitro 15d-PGJ2 increased the expression of FOXP3, GITR, and CTLA-4 in the CD4+CD25- population, suggesting the induction of Tregs on conventional T cells. Prostanoid addition to CD4+CD25- cells selectively suppressed Th17 differentiation and promoted the enhancement of FOXP3 under polarization conditions. Thus, 15d-PGJ2 ameliorated symptoms of collagen-induced arthritis by regulating Th17 differentiation, concomitant with the induction of Tregs, and, consequently, protected mice from diseases aggravation. Altogether, these results indicate that 15d-PGJ2 may represent a potential therapeutic strategy in RA.


Methylthioadenosine phosphorylase deficiency in human leukemias and solid tumors.
5'-Methylthioadenosine (MTA) is a naturally occurring nucleoside which is degraded by MTA phosphorylase (MTAase) to adenine and methylthioribose-1-phosphate in all normal mammalian cells. These products of the phosphorylytic cleavage of MTA are recycled to the nucleotide pool and methionine, respectively. Thus, supplemental MTA could theoretically be utilized by MTAase-containing cells as a source of methionine and adenine. In fact, in vitro experiments have shown that MTAase-containing cells proliferate normally in methionine-free medium if MTA is added to the cultures (M. K. Riscoe and A. J. Ferro, J. Biol. Chem., 259: 5465-5471, 1984). In contrast, MTAase-deficient malignant cell lines do not proliferate under these conditions. In light of these observations and the recent demonstration (N. Kamatani et al., Blood, 60: 1387-1391, 1982) that a proportion of acute lymphoblastic leukemias lack MTAase, we wished to determine if this enzyme deficiency occurs in a variety of human neoplasms. Accordingly, malignant cells from eight patients with acute nonlymphocytic leukemia and ten patients with various solid tumors were assayed for MTAase activity. Samples from one of the eight acute nonlymphocytic leukemia patients and three of the 10 solid tumor patients (one with melanoma, one with squamous cell lung cancer, and one with adenocarcinoma of the rectum) had undetectable MTAase activity. In contrast, erythrocytes, neutrophils, and monocytes isolated from normal subjects and from patients with immunodeficiency syndromes or cancer all contained enzyme activity. In addition, the methods of preservation, storage, and cell disruption did not affect MTAase activity. These observations confirm and extend the findings of Kamatani et al. (Blood, 60: 1387-1391, 1982) by demonstrating that MTAase deficiency occurs in a variety of human malignancies including acute nonlymphocytic leukemia and solid tumors. This metabolic difference between normal and malignant cells may be therapeutically exploitable.


Food quality affects secondary consumers even at low quantities: an experimental test with larval European lobster.
The issues of food quality and food quantity are crucial for trophic interactions. Although most research has focussed on the primary producer-herbivore link, recent studies have shown that quality effects at the bottom of the food web propagate to higher trophic levels. Negative effects of poor food quality have almost exclusively been demonstrated at higher food quantities. Whether these negative effects have the same impact at low food availability in situations where the majority if not all of the resources are channelled into routine metabolism, is under debate. In this study a tri-trophic food chain was designed, consisting of the algae Rhodomonas salina, the copepod Acartia tonsa and freshly hatched larvae of the European lobster Homarus gammarus. The lobster larvae were presented with food of two different qualities (C:P ratios) and four different quantities to investigate the combined effects of food quality and quantity. Our results show that the quality of food has an impact on the condition of lobster larvae even at very low food quantities. Food with a lower C:P content resulted in higher condition of the lobster larvae regardless of the quantity of food. These interacting effects of food quality and food quantity can have far reaching consequences for ecosystem productivity.


Studies on a novel DNA polymerase inhibitor group, synthetic sulfoquinovosylacylglycerols: inhibitory action on cell proliferation.
Some chemically synthesized sulfoquinovosylmonoacylglycerols (SQMG)-sulfoquinovosyldiacylglycerols (SQDG) have been reported to selectively and strongly inhibit the activities of mammalian DNA polymerases alpha and beta in vitro. In this study, using human cancer cell lines, we investigated the effects of SQMG-SQDG on the DNA polymerase in the cells. In the presence of n-decane, the IC(50) values on cell growth were approximately 1-5 microM for SQMG and about 0.3-1 microM for SQDG. The values were almost the same as the in vitro enzyme inhibitory levels. The cell lines were arrested in early S-phase by SQMG-SQDG at the concentrations of 0.1-4.7 microM in a manner dependent on incubation time, suggesting that SQMG-SQDG blocked the primary step of DNA replication by inhibiting DNA polymerase, possibly alpha-type. We also demonstrated the localization of SQMG in the cell using the fluorescent SQMG analog, SQMGalpha-NBDD, which was synthesized in our laboratory. SQMGalpha-NBDD was localized in the nucleus and on the nuclear surface, but the binding site seemed not to be the DNA/chromatin, suggesting that the SQMG-SQDG might interact with molecules located close to the DNA/chromatin and on the nuclear surface. These results suggested a correlation between the in vitro biochemical action of the SQMG-SQDGs and their intracellular mode of action.


Pharmacogenetic profile of a South Portuguese population: results from the pilot study of the European Health Examination Survey in Portugal.
The genetic inter-individual variability of drug response can lead to therapeutic failure or adverse drug reactions (ADRs). The aims of this study were to assess the pharmacogenetic profile of a South Portuguese population according to established dosing guidelines for commonly prescribed drugs and to compare it with that of previously genotyped populations. A cross-sectional study was developed in the context of the Portuguese Component of the European Health Examination Survey (EHES). A total of 47 pharmacogenetically relevant variants in 23 different genes were genotyped in 208 participants. Allelic and genotypic frequencies were calculated, and the pharmacogenetic profile of the participants was defined. A comparative analysis was conducted through electronic database search. Pairwise Fst calculations were performed to assess the genetic distance between populations. We found a significant small differentiation between the Portuguese regional populations regarding CYP2C9 rs1057910, CYP2D6 rs3892097, MTHFR rs1801133 and F5 rs6025. When consid-ering 4 HapMap populations, ADH1B rs2066702, ADH1B rs1229984, NAT2 rs1799931 and VKORC1 rs9923231 displayed a significant population differentiation. We found that 18.9% of the participants are intermediate or poor metabolizers for at least 3 drugs simultaneously and that 84.6% of the participants have at least one therapeutic failure or ADR risk allele for the considered drugs. There is a high prevalence of risk alleles associated with an altered drug metabolism regarding drugs largely used by the South Portuguese population. This knowledge contributes to the prediction of their clinical efficacy and/or toxicity, optimizing therapeutic response while improving cost-effectiveness.


Reproductive health awareness among rural school going adolescents of Vadodara district.
To identify the reproductive health issues associated with adolescence and their readiness to avail services like Adolescent Friendly Clinic (AFC) among rural school going children. A quantitative survey was carried out using a self-administered structured questionnaire among 768 (428 boys and 340 girls) students from 15 schools by systematic random sampling from schools (3 schools from 5 talukas). Focus group discussions, 5 each with adolescent boys and girls and teachers were held. Only 31% of the boys and 33% of the girls mentioned that they had heard about contraception. More than half of the adolescent boys and girls knew correctly about various modes of transmission of HIV/AIDS. A large proportion of boys and girls have mentioned changes in the opposite sex such as increase in height, change in voice, breast development, and growth of facial hair, growth of hair in private parts, onset of menstruation in girls, etc. Nearly 70% of adolescents were ready to use AFC. Teachers perceived that adolescents become curious about the changes taking place in them, but they lack information and opportunities for open-discussions to get answers to their queries related to reproductive health. They are willing to take help from teachers but teachers are not equipped with knowledge nor are they comfortable discussing these issues with their students. Information on the human reproductive system and related issues on reproductive health need special attention. Teachers' sensitization to "adolescent health care" is required.


Characterising the dynamics of EEG waveforms as the path through parameter space of a neural mass model: application to epilepsy seizure evolution.
In this paper we propose that the dynamic evolution of EEG activity during epileptic seizures may be characterised as a path through parameter space of a neural mass model, reflecting gradual changes in underlying physiological mechanisms. Previous theoretical studies have shown how boundaries in parameter space of the model (so-called bifurcations) correspond to transitions in EEG waveforms between apparently normal, spike and wave and subsequently poly-spike and wave activity. In the present manuscript, we develop a multi-objective genetic algorithm that can estimate parameters of an underlying model from clinical data recordings. A standard approach to this problem is to transform both clinical data and model output into the frequency domain and then choose parameters that minimise the difference in their respective power spectra. Instead in the present manuscript, we estimate parameters in the time domain, their choice being determined according to the best fit obtained between the model output and specific features of the observed EEG waveform. This results in an approximate path through the bifurcation plane of the model obtained from clinical data. We present comparisons of such paths through parameter space from separate seizures from an individual subject, as well as between different subjects. Differences in the path reflect subtleties of variation in the dynamics of EEG, which at present appear indistinguishable using standard clinical techniques.


Why screening tests to predict injury do not work-and probably never will…: a critical review.
This paper addresses if and how a periodic health examination to screen for risk factors for injury can be used to mitigate injury risk. The key question asked is whether it is possible to use screening tests to identify who is at risk for a sports injury-in order to address the deficit through a targeted intervention programme. The paper demonstrates that to validate a screening test to predict and prevent sports injuries, at least 3 steps are needed. First, a strong relationship needs to be demonstrated in prospective studies between a marker from a screening test and injury risk (step 1). Second, the test properties need to be examined in relevant populations, using appropriate statistical tools (step 2). Unfortunately, there is currently no example of a screening test for sports injuries with adequate test properties. Given the nature of potential screening tests (where test performance is usually measured on a continuous scale from low to high), substantial overlap is to be expected between players with high and low risk of injury. Therefore, although there are a number of tests demonstrating a statistically significant association with injury risk, and therefore help the understanding of causative factors, such tests are unlikely to be able to predict injury with sufficient accuracy. The final step needed is to document that an intervention programme targeting athletes identified as being at high risk through a screening programme is more beneficial than the same intervention programme given to all athletes (step 3). To date, there is no intervention study providing support for screening for injury risk.


Interaction between MTHFR 677C>T, PON1 192Q>R and PON1 55L>M polymorphisms and its effect on non-recurrent spontaneous abortion in Mexican women.
MTHFR is a key enzyme in folate metabolism. Some genetic polymorphisms code for a less efficient enzyme, increasing serum concentrations of homocysteine. This has been associated with inadequate feto-maternal circulation and increased risk of spontaneous abortion. Paroxonase 1 (PON1) is a multifunctional enzyme that can detoxify homocysteine through its homocysteine thiolactonase activity. We evaluate the association between MTHFR 677 C>T polymorphisms and non-recurrent spontaneous abortion and its interaction with PON1 polymorphisms involved in homocysteine metabolism in women living in floricultural areas in Mexico. Sociodemographic, reproductive history, folic acid consumption during pregnancy and environmental exposure data of 264 women who had been pregnant sometime during the 10 years prior to study enrolment were collected. MTHFR 677 C>T, PON1 192Q>R and PON1 55L>M genotypes were determined by PCR amplification. Information on pregnancy outcome and maternal genotypes was obtained for 484 pregnancies: 34 non-recurrent spontaneous abortions (gestational age < 20 weeks) and 450 controls. GEE models were used to evaluate the association between MTHFR polymorphism and non-recurrent spontaneous abortion, and its interaction with PON1 polymorphisms. After adjusting for potential confounders, no significant association was found between the MTHFR 677 C>T maternal polymorphism and non-recurrent spontaneous abortion (OR CT vs CC= 0.39, 95% CI: 0.14-1.05; OR TT vs CC = 0.63, 95% CI: 1.22-1.80). No interactions with PON1 192Q>R or PON1 55L>M polymorphisms were identified (p for interaction = 0.88 and 0.41, respectively). PON1 55L>M maternal polymorphism was associated with higher risk of spontaneous abortion (OR LM/MM vs LL = 4.14, 95% CI: 1.49-11.54). Our results do not demonstrate an interaction between the MTHFR 677 C>T and PON1 192Q>R or PON1 55L>M maternal polymorphisms neither an independent association of MTHFR 677 C>T polymorphism with non-recurrent spontaneous abortion, whereas PON1 55LM/MM maternal genotype increase the odds of this event.


Ontogenetic development of auditory sensitivity and sound production in the squeaker catfish Synodontis schoutedeni.
Surveys of ontogenetic development of hearing and sound production in fish are scarce, and the ontogenetic development of acoustic communication has been investigated in only two fish species so far. Studies on the labyrinth fish Trichopsis vittata and the toadfish Halobatrachus didactylus show that the ability to detect conspecific sounds develops during growth. In otophysine fish, which are characterized by Weberian ossicles and improved hearing sensitivities, the ontogenetic development of sound communication has never been investigated. We analysed the ontogeny of the auditory sensitivity and vocalizations in the mochokid catfish Synodontis schoutedeni. Mochokid catfishes of the genus Synodontis are commonly called squeakers because they produce broadband stridulation sounds during abduction and adduction of pectoral fin spines. Fish from six different size groups - from 22 mm standard length to 126 mm - were studied. Hearing thresholds were measured between 50 Hz and 6 kHz using the auditory evoked potentials recording technique; stridulation sounds were recorded and their sound pressure levels determined. Finally, absolute sound power spectra were compared to auditory sensitivity curves within each size group. The smallest juveniles showed the poorest hearing abilities of all size groups between 50 and 1,000 Hz and highest hearing sensitivity at 5 and 6 kHz. The duration of abduction and adduction sounds and the pulse period increased and sound pressure level (in animals smaller than 58 mm) increased, while the dominant frequency of sounds decreased with size in animals larger than 37 mm. Comparisons between audiograms and sound spectra revealed that the most sensitive frequencies correlate with the dominant frequencies of stridulation sounds in all S. schoutedeni size groups and that all specimens are able to detect sounds of all size groups. This study on the squeaker catfish S. schoutedeni is the first to demonstrate that absolute hearing sensitivity changes during ontogeny in an otophysine fish. This contrasts with prior studies on two cypriniform fish species in which no such change could be observed. Furthermore, S. schoutedeni can detect conspecific sounds at all stages of development, again contrasting with prior findings in fishes.


Nonlinear effects of particle shape angularity in sheared granular media.
We analyze the effects of particle shape angularity on the macroscopic shear behavior and texture of granular packings simulated by means of the contact dynamics method. The particles are regular polygons with an increasing number of sides ranging from 3 (triangles) to 60. The packings are analyzed in the steady shear state in terms of their shear strength, packing fraction, connectivity, and fabric and force anisotropies, as functions of the angularity. An interesting finding is that the shear strength increases with angularity up to a maximum value and saturates as the particles become more angular (below six sides). In contrast, the packing fraction declines towards a constant value, so that the packings of more angular particles are looser but have higher shear strength. We show that the increase of the shear strength at low angularity is due to an increase of both contact and force anisotropies and the saturation of the shear strength for higher angularities is a consequence of a rapid falloff of the contact and normal force anisotropies compensated for by an increase of the tangential force anisotropy. This transition reflects clearly the rather special geometrical properties of these highly angular shapes, implying that the stability of the packing relies strongly on the side-side contacts and the mobilization of friction forces.


Oxidative stress and inflammation contribute to lung toxicity after a common breast cancer chemotherapy regimen.
Delayed pulmonary toxicity syndrome after high-dose chemotherapy (HDC) and autologous hematopoietic support occurs in up to 64% of women with advanced-stage breast cancer. Using a similar, but nonmyeloablative, HDC treatment regimen in mice, we found both immediate and persistent lung injury, coincident with marked decreases in lung tissue glutathione reductase activity and accompanied by increases in lung oxidized glutathione, bronchoalveolar lavage (BAL) lipid peroxidation, and BAL total cell counts. Most interestingly, at 6 wk, BAL total cell counts had increased fourfold, with lymphocyte cell counts increasing >11-fold. A single supplemental dose of glutathione prevented early lung injury at 48 h but showed no lung-protective effects at 6 wk, whereas single doses of other thiol-sparing agents (Ethyol and glutathione monoethyl ester) showed no benefit. These data suggest that this HDC regimen results in acute and persistent lung toxicity, induced in part by oxidative stress, that culminates with an acute lung cellular inflammatory response. Continuous glutathione supplementation and/or attenuation of the delayed pulmonary inflammatory response may prove beneficial in preventing lung toxicity after the use of these chemotherapeutic agents.


Beta-scission of side-chain alkoxyl radicals on peptides and proteins results in the loss of side-chains as aldehydes and ketones.
Exposure of proteins to radicals in the presence of O(2) results in side-chain oxidation and backbone fragmentation; the interrelationship between these processes is not fully understood. Recently, initial attack on Ala side-chains was shown to give alpha-carbon radicals (and hence backbone cleavage) and formaldehyde, via the formation and subsequent beta-scission, of C-3 alkoxyl radicals. We now show that this side-chain to backbone damage transfer, is a general mechanism for aliphatic side-chains. Oxidation of Val, Leu, and Asp residues by HO(*)/O(2) results in the release of a family of carbonyls (including formaldehyde, acetone, isobutyraldehyde, and glyoxylic acid) via the formation, and subsequent beta-scission of alkoxyl radicals. The concentration of these products increases with the HO(*) flux. The release of multiple carbonyls confirms the occurrence of oxidation at C-3 and C-4 for Val, and these sites, plus C-5, for Leu. The detection of glyoxylic acid and CO(2)(-*) from Asp demonstrates the occurrence of competing beta-scission processes for the Asp C-3 alkoxyl radical. The yield of hydroperoxides and released carbonyls account for 10-145% of the initial HO(*). The greater than 100% yields confirm the occurrence of chain reactions in peptide/protein oxidation, with more than one residue being damaged per initiating radical.


Affinity Maturation of a Potent Family of HIV Antibodies Is Primarily Focused on Accommodating or Avoiding Glycans.
The high-mannose patch on the HIV-1 envelope (Env) glycoprotein is the epicenter for binding of the potent broadly neutralizing PGT121 family of antibodies, but strategies for generating such antibodies by vaccination have not been defined. We generated structures of inferred antibody intermediates by X-ray crystallography and electron microscopy to elucidate the molecular events that occurred during evolution of this family. Binding analyses revealed that affinity maturation was primarily focused on avoiding, accommodating, or binding the N137 glycan. The overall antibody approach angle to Env was defined very early in the maturation process, yet some variation evolved in the PGT121 family branches that led to differences in glycan specificities in their respective epitopes. Furthermore, we determined a crystal structure of the recombinant BG505 SOSIP.664 HIV-1 trimer with a PGT121 family member at 3.0 Å that, in concert with these antibody intermediate structures, provides insights to advance design of HIV vaccine candidates.


Genetic influences on response to novel objects and dimensions of personality in Papio baboons.
Behavioral variation within and between populations and species of the genus Papio has been studied extensively, but little is known about the genetic causes of individual- or population-level differences. This study investigates the influence of genetic variation on personality (sometimes referred to as temperament) in baboons and identifies a candidate gene partially responsible for the variation in that phenotype. To accomplish these goals, we examined individual variation in response to both novel objects and an apparent novel social partner (using a mirror test) among pedigreed baboons (n = 578) from the Southwest National Primate Research Center. We investigated the frequency and duration of individual behaviors in response to novel objects and used multivariate factor analysis to identify trait-like dimensions of personality. Exploratory factor analysis identified two distinct dimensions of personality within this population. Factor 1 accounts for 46.8 % of the variance within the behavioral matrix, and consists primarily of behaviors related to the "boldness" of the subject. Factor 2 accounts for 18.8 % of the variation, and contains several "anxiety" like behaviors. Several specific behaviors, and the two personality factors, were significantly heritable, with the factors showing higher heritability than most individual behaviors. Subsequent analyses show that the behavioral reactions observed in the test protocol are associated with animals' social behavior observed later in their home social groups. Finally we used linkage analysis to map quantitative trait loci for the measured phenotypes. Single nucleotide polymorphisms in a positional candidate gene (SNAP25) are associated with variation in one of the personality factors, and CSF levels of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol. This study documents heritable variation in personality among baboons and suggests that sequence variation in SNAP25 may influence differences in behavior and neurochemistry in these nonhuman primates.


Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation, despite immunosuppression, is associated with autoantibodies and pathogenic autoreactive CD4 T-cells.
To investigate if recurrent autoimmunity explained hyperglycemia and C-peptide loss in three immunosuppressed simultaneous pancreas-kidney (SPK) transplant recipients. We monitored autoantibodies and autoreactive T-cells (using tetramers) and performed biopsy. The function of autoreactive T-cells was studied with in vitro and in vivo assays. Autoantibodies were present pretransplant and persisted on follow-up in one patient. They appeared years after transplantation but before the development of hyperglycemia in the remaining patients. Pancreas transplant biopsies were taken within approximately 1 year from hyperglycemia recurrence and revealed beta-cell loss and insulitis. We studied autoreactive T-cells from the time of biopsy and repeatedly demonstrated their presence on further follow-up, together with autoantibodies. Treatment with T-cell-directed therapies (thymoglobulin and daclizumab, all patients), alone or with the addition of B-cell-directed therapy (rituximab, two patients), nonspecifically depleted T-cells and was associated with C-peptide secretion for >1 year. Autoreactive T-cells with the same autoantigen specificity and conserved T-cell receptor later reappeared with further C-peptide loss over the next 2 years. Purified autoreactive CD4 T-cells from two patients were cotransplanted with HLA-mismatched human islets into immunodeficient mice. Grafts showed beta-cell loss in mice receiving autoreactive T-cells but not control T-cells. We demonstrate the cardinal features of recurrent autoimmunity in three such patients, including the reappearance of CD4 T-cells capable of mediating beta-cell destruction. Markers of autoimmunity can help diagnose this underappreciated cause of graft loss. Immune monitoring during therapy showed that autoimmunity was not resolved by the immunosuppressive agents used.


Diagnosis of obstructive coronary artery disease using computed tomography angiography in patients with stable chest pain depending on clinical probability and in clinically important subgroups: meta-analysis of individual patient data.
To determine whether coronary computed tomography angiography (CTA) should be performed in patients with any clinical probability of coronary artery disease (CAD), and whether the diagnostic performance differs between subgroups of patients. Prospectively designed meta-analysis of individual patient data from prospective diagnostic accuracy studies. Medline, Embase, and Web of Science for published studies. Unpublished studies were identified via direct contact with participating investigators. Prospective diagnostic accuracy studies that compared coronary CTA with coronary angiography as the reference standard, using at least a 50% diameter reduction as a cutoff value for obstructive CAD. All patients needed to have a clinical indication for coronary angiography due to suspected CAD, and both tests had to be performed in all patients. Results had to be provided using 2×2 or 3×2 cross tabulations for the comparison of CTA with coronary angiography. Primary outcomes were the positive and negative predictive values of CTA as a function of clinical pretest probability of obstructive CAD, analysed by a generalised linear mixed model; calculations were performed including and excluding non-diagnostic CTA results. The no-treat/treat threshold model was used to determine the range of appropriate pretest probabilities for CTA. The threshold model was based on obtained post-test probabilities of less than 15% in case of negative CTA and above 50% in case of positive CTA. Sex, angina pectoris type, age, and number of computed tomography detector rows were used as clinical variables to analyse the diagnostic performance in relevant subgroups. Individual patient data from 5332 patients from 65 prospective diagnostic accuracy studies were retrieved. For a pretest probability range of 7-67%, the treat threshold of more than 50% and the no-treat threshold of less than 15% post-test probability were obtained using CTA. At a pretest probability of 7%, the positive predictive value of CTA was 50.9% (95% confidence interval 43.3% to 57.7%) and the negative predictive value of CTA was 97.8% (96.4% to 98.7%); corresponding values at a pretest probability of 67% were 82.7% (78.3% to 86.2%) and 85.0% (80.2% to 88.9%), respectively. The overall sensitivity of CTA was 95.2% (92.6% to 96.9%) and the specificity was 79.2% (74.9% to 82.9%). CTA using more than 64 detector rows was associated with a higher empirical sensitivity than CTA using up to 64 rows (93.4% v 86.5%, P=0.002) and specificity (84.4% v 72.6%, P<0.001). The area under the receiver-operating-characteristic curve for CTA was 0.897 (0.889 to 0.906), and the diagnostic performance of CTA was slightly lower in women than in with men (area under the curve 0.874 (0.858 to 0.890) v 0.907 (0.897 to 0.916), P<0.001). The diagnostic performance of CTA was slightly lower in patients older than 75 (0.864 (0.834 to 0.894), P=0.018 v all other age groups) and was not significantly influenced by angina pectoris type (typical angina 0.895 (0.873 to 0.917), atypical angina 0.898 (0.884 to 0.913), non-anginal chest pain 0.884 (0.870 to 0.899), other chest discomfort 0.915 (0.897 to 0.934)). In a no-treat/treat threshold model, the diagnosis of obstructive CAD using coronary CTA in patients with stable chest pain was most accurate when the clinical pretest probability was between 7% and 67%. Performance of CTA was not influenced by the angina pectoris type and was slightly higher in men and lower in older patients. PROSPERO CRD42012002780.


Genetic diversity in human erythrocyte pyruvate kinase.
Previously, we have shown that pyruvate kinase, liver and red cell isoform (PKLR) deficiency protects mice in vivo against blood-stage malaria, and observed that reduced PKLR function protects human erythrocytes against Plasmodium falciparum replication ex vivo. Here, we have sequenced the human PKLR gene in 387 individuals from malaria-endemic and other regions in order to assess genetic variability in different geographical regions and ethnic groups. Rich genetic diversity was detected in PKLR, including 59 single-nucleotide polymorphisms and several loss-of-function variants (frequency 1.5%). Haplotype distribution and allele frequency varied considerably with geography. Neutrality testing suggested positive selection of the genein the sub-Saharan African and Pakistan populations. It is possible that such positive selection involves the malarial parasite.


Leishmania major intracellular survival is not altered in SHP-1 deficient mev or CD45-/- mice.
Protozoan parasites of the genus Leishmania escape from the immune response by interfering with signal transduction pathways of its host cell, the macrophage, thereby establishing permissive conditions for intracellular survival. Inhibition of macrophage activation after Leishmania infection has been suggested to require activation of the host cell phosphatase SHP-1. However, by utilizing infections of SHP-1 deficient (me(v)) and CD45 null mutant mice or macrophages, we provide evidence that intracellular survival of Leishmania major is not generally dependent on these cellular phosphatases.


The struggle to govern the commons.
Human institutions--ways of organizing activities--affect the resilience of the environment. Locally evolved institutional arrangements governed by stable communities and buffered from outside forces have sustained resources successfully for centuries, although they often fail when rapid change occurs. Ideal conditions for governance are increasingly rare. Critical problems, such as transboundary pollution, tropical deforestation, and climate change, are at larger scales and involve nonlocal influences. Promising strategies for addressing these problems include dialogue among interested parties, officials, and scientists; complex, redundant, and layered institutions; a mix of institutional types; and designs that facilitate experimentation, learning, and change.


Realizing the therapeutic potential of rare earth elements in designing nanoparticles to target and treat glioblastoma.
The prognosis of brain cancer glioblastoma (GBM) is poor, and despite intense research, there have been no significant improvements within the last decade. This stasis implicates the need for more novel therapeutic investigation. One such option is the use of nanoparticles (NPs), which can be beneficial due to their ability to penetrate the brain, overcome the blood-brain barrier and take advantage of the enhanced permeation and retention effect of GBM to improve specificity. Rare earth elements possess a number of interesting natural properties due to their unique electronic configuration, which may prove therapeutically advantageous in an NP formulation. The underexplored exciting potential for rare earth elements to augment the therapeutic potential of NPs in GBM treatment is discussed in this review.


Optical theorem for acoustic non-diffracting beams and application to radiation force and torque.
Acoustical and optical non-diffracting beams are potentially useful for manipulating particles and larger objects. An extended optical theorem for a non-diffracting beam was given recently in the context of acoustics. The theorem relates the extinction by an object to the scattering at the forward direction of the beam's plane wave components. Here we use this theorem to examine the extinction cross section of a sphere centered on the axis of the beam, with a non-diffracting Bessel beam as an example. The results are applied to recover the axial radiation force and torque on the sphere by the Bessel beam.


Localization of motor-related proteins and associated complexes to active, but not inactive, centromeres.
Multicentric chromosomes are often found in tumor cells and certain cell lines. How they are generated is not fully understood, though their stability suggests that they are non-functional during chromosome segregation. Growing evidence has implicated microtubule motor proteins in attachment of chromosomes to the mitotic spindle and in chromosome movement. To better understand the molecular basis for the inactivity of centromeres associated with secondary constrictions, we have tested these structures by immunofluorescence microscopy for the presence of motor complexes and associated proteins. We find strong immunoreactivity at the active, but not inactive, centromeres of prometaphase multicentric chromosomes using antibodies to the cytoplasmic dynein intermediate chains, three components of the dynactin complex (dynamitin, Arp1 and p150 Glued ), the kinesin-related proteins CENP-E and MCAK and the proposed structural and checkpoint proteins HZW10, CENP-F and Mad2p. These results offer new insight into the assembly and composition of both primary and secondary constrictions and provide a molecular basis for the apparent inactivity of the latter during chromosome segregation.


Idiotypic intravaginal vaccination to protect against candidal vaginitis by secretory, yeast killer toxin-like anti-idiotypic antibodies.
The principles of idiotypic (Id) vaccination were used to immunize against vaginitis caused by Candida albicans, a widespread and sometimes intractable disease in women. To this aim, a murine mAb (KT4, IgG1) neutralizing in vitro the anti-Candida activity of a yeast killer toxin (YKT) was used as an Id vaccine to elicit Abs with toxin-like activity in a rat vaginitis model. Nonimmunized and isotype-matched, irrelevant mAb-immunized rats served as controls. An effective protection was obtained in Id-vaccinated animals, as demonstrated by a highly significant decrease in vaginal Candida CFU compared with controls. The protection was associated with rising vaginal titers of anti-idiotypic Abs (IdAb), prevalently of the IgA isotype, that were able to passively transfer the protective state to nonimmunized animals. The vaginal IdAb possessed YKT-like activity because they were able to kill in vitro the challenging fungal cells, and this killing was neutralized by the mAb KT4. Overall, these data demonstrate that secretory IdAb elicited by intravaginal Id vaccination with mAb KT4 protected the rats from the infectious challenge with Candida albicans by molecular mimicking YKT activity as its internal image.


Laparoscopic hepatectomy in a morbidly obese patient with liver cirrhosis: A case report.
Cirrhotic patients constitute a high-risk population, and present a major challenge for the performance of minimally invasive laparoscopic resections due to difficulties in parenchymal transection. The present study describes the case of a 71-year-old morbidly obese male patient who was referred to our department with a hepatic mass identified on routine abdominal ultrasound. Abdominal computer tomography and magnetic resonance imaging confirmed a mass in segments V-VI of the liver, highly suspicious for HCC. The patient's past medical history additionally included non-alcoholic steatohepatitis, diabetes mellitus and arterial hypertension and myocardial infarction. The patient's body mass index was 45 kg/m2, and the American Society of Anesthesiologists' classification of preoperative risk was 3. The patient underwent laparoscopic resection of segments V-VI and cholecystectomy. Two years postoperatively, the patient remains disease-free and in excellent condition. To the best of our knowledge, this is the first report on laparoscopic liver resection for such a morbidly obese patient in the context of advanced liver cirrhosis.


Current patterns of diet in community-dwelling older men and women: results from the Hertfordshire Cohort Study.
dietary patterns analysis takes account of the combined effects of foods and may be a more meaningful way of assessing dietary exposure than considering individual nutrients. Little is known about the dietary patterns of older adults in the UK. to describe the dietary patterns of a population of community-dwelling older men and women and to examine factors associated with compliance with these patterns. 3,217 men and women aged 59-73 years who were participants in the Hertfordshire Cohort Study. diet was assessed using an administered food frequency questionnaire; dietary patterns were identified using principal component analysis. two dietary patterns were identified. The first was characterised by high consumption of fruit, vegetables, oily fish and wholemeal cereals ('prudent' pattern); the second was characterised by high consumption of vegetables, processed and red meat, fish and puddings ('traditional' pattern). High 'prudent' diet scores were more common in women, in men and women in non-manual classes and in non-smokers (all P < 0.05), whilst high 'traditional' diet scores were more common in men, in men and women who had partners and were associated with higher alcohol consumption (all P < 0.05). we have described large variations in food consumption and nutrient intake amongst older adults that are likely to have implications for future health. The specific socio-demographic correlates of the dietary patterns provide insights into the contexts within which good and poor diets exist, and may help in the identification of opportunities for dietary intervention.


The Psychological Science Accelerator: Advancing Psychology through a Distributed Collaborative Network.
Concerns have been growing about the veracity of psychological research. Many findings in psychological science are based on studies with insufficient statistical power and nonrepresentative samples, or may otherwise be limited to specific, ungeneralizable settings or populations. Crowdsourced research, a type of large-scale collaboration in which one or more research projects are conducted across multiple lab sites, offers a pragmatic solution to these and other current methodological challenges. The Psychological Science Accelerator (PSA) is a distributed network of laboratories designed to enable and support crowdsourced research projects. These projects can focus on novel research questions, or attempt to replicate prior research, in large, diverse samples. The PSA's mission is to accelerate the accumulation of reliable and generalizable evidence in psychological science. Here, we describe the background, structure, principles, procedures, benefits, and challenges of the PSA. In contrast to other crowdsourced research networks, the PSA is ongoing (as opposed to time-limited), efficient (in terms of re-using structures and principles for different projects), decentralized, diverse (in terms of participants and researchers), and inclusive (of proposals, contributions, and other relevant input from anyone inside or outside of the network). The PSA and other approaches to crowdsourced psychological science will advance our understanding of mental processes and behaviors by enabling rigorous research and systematically examining its generalizability.


Management options for malignant pleural mesothelioma: clinical and cost considerations.
Malignant pleural mesothelioma (MPM) is a resistant form of lung cancer that is often related to prior asbestos exposure. While surgical resection and radiotherapy techniques have been refined in recent years, neither has been proven to significantly extend patient survival compared with untreated controls. Until the release of pemetrexed in 2004, even combination chemotherapy regimens often resulted in a response rate of <20%. A recent phase III trial documented a 41.3% response rate for cisplatin plus pemetrexed. In the future, new multimodality regimens featuring novel targeted therapies directed against molecular targets, such as the vascular endothelial growth factor, hold the greatest promise for improved outcomes in MPM. The standard radiographic assessment of response to MPM therapy remains a poor surrogate for clinically relevant endpoints such as median survival. Furthermore, it is not currently known whether aggressive multimodality treatment for MPM will improve survival or quality of life above and beyond symptomatic care. Ongoing clinical trials are comparing chemotherapy and surgery with supportive care in an effort to define the role of different therapies in MPM. MPM treatment is a costly public health issue; after efficacy is proven, additional studies are needed to measure the cost effectiveness of MPM treatment regimens.


Histochemical staining and quantification of plant mitochondrial respiratory chain complexes using blue-native polyacrylamide gel electrophoresis.
Our knowledge of the respiratory chain and associated defects depends on the study of the multisubunit protein complexes in the inner mitochondrial membrane. Functional analysis of the plant mitochondrial respiratory chain has been successfully achieved by a combination of blue-native polyacrylamide gel electrophoresis (BN-PAGE) for separation of the protein complexes, and in-gel histochemical staining of the enzyme activities. We have optimized this powerful technique by determining linear ranges of amount of protein and enzyme activity for each respiratory complex. Time courses of the in-gel enzyme activities were also performed to determine optimal reaction times. Using the in-gel activity staining method we have previously shown decreased activity of complex V (F(1)F(0)-ATPase) in male-sterile sunflowers (Sabar et al., 2003). Here we have identified unique supercomplexes comprising complex IV (cytochrome c oxidase) in sunflower mitochondria. This method therefore represents a reliable tool for the diagnosis of respiratory dysfunction. In addition, the wider application of BN-PAGE in combination with enzyme activity staining is discussed.


Transgastric endoscopic peritoneoscopy does not require decontamination of the stomach in humans.
Natural orifice translumenal endoscopic surgery (NOTES) is a rapidly evolving field that provides endoscopic access to the peritoneum via a natural orifice. One important requirement of this technique is the need to minimize the risk of clinically significant peritoneal contamination. We report the bacterial load and contamination of the peritoneal cavity in ten patients who underwent diagnostic transgastric endoscopic peritoneoscopy. Patients participating in this trial were scheduled to undergo diagnostic laparoscopy for evaluation of presumed pancreatic cancer. Findings at diagnostic laparoscopy were compared with those of diagnostic transgastric endoscopic peritoneoscopy, using an orally placed gastroscope, blinding the endoscopist to the laparoscopic findings. We performed no gastric decontamination. Diagnostic findings, operative times, and clinical course were recorded. Gastroscope and peritoneal fluid aspirates were obtained prior to and after the gastrotomy. Each sample was sent for bacterial colony counts, culture, and identification of species. Ten patients, with an average age of 63.7 years, have completed the protocol. All patients underwent diagnostic laparoscopy followed by successful transgastric access and diagnostic peritoneoscopy. The average time for laparoscopy was 7.2 min, compared with 18 min for transgastric instrumentation. Bacterial sampling was obtained in all ten patients. The average number of colony-forming units (CFU) in the gastroscope aspirate was 132.1 CFU/ml, peritoneal aspirates prior to creation of a gastrotomy showed 160.4 CFU/ml, and peritoneal sampling after gastrotomy had an average of 642.1 CFU/ml. There was no contamination of the peritoneal cavity with species isolated from the gastroscope aspirate. No infectious complications or leaks were noted at 30-day follow-up. There was no clinically significant contamination of the peritoneal cavity from the gastroscope after transgastric endoscopic instrumentation in humans. Transgastric instrumentation does contaminate the abdominal cavity but, the pathogens do not mount a clinically significant response in terms of either the species or the bacterial load.


Influence of chloride ions on the synthesis of colloidal branched CdSe/CdS nanocrystals by seeded growth.
We studied the influence of chloride ions (Cl(-)), introduced as CdCl(2), on the seeded growth synthesis of colloidal branched CdSe(core)/CdS(pods) nanocrystals. This is carried out by growing wurtzite CdS pods on top of preformed octahedral sphalerite CdSe seeds. When no CdCl(2) is added, the synthesis of multipods has a low reproducibility, and the side nucleation of CdS nanorods is often observed. At a suitable concentration of CdCl(2), octapods are formed and they are stable in solution during the synthesis. Our experiments indicate that Cl(-) ions introduced in the reaction reduce the availability of Cd(2+) ions in solution, most likely via formation of strong complexes with both Cd and the various surfactants. This prevents homogeneous nucleation of CdS nanocrystals, so that the heterogeneous nucleation of CdS pods on top of the CdSe seeds is the preferred process. Once such optimal concentration of CdCl(2) is set for a stable growth of octapods, the pod lengths can be tuned by varying the relative ratios of the various alkyl phosphonic acids used. Furthermore, at higher concentrations of CdCl(2) added, octapods are initially formed, but many of them evolve into tetrapods over time. This transformation points to an additional role of Cl species in regulating the growth rate and stability of various crystal facets of the CdS pods.


Confidentiality for mental health concerns in adolescent primary care.
Guidelines from several national professional groups and a patchwork of state laws support the option to provide confidential mental healthcare for adolescents as a way to reduce barriers to treatment. These guidelines do not, however, help doctors decide when and to what extent confidentiality might be appropriate. We propose a set of practical considerations that clinicians can use to develop and justify confidentiality and family involvement in individual cases. Use of this framework may increase clinician comfort in discussing confidentiality and mental health topics with adolescents, and thus reduce barriers to the management of mental health problems in adolescent primary care.


Estimating The Potential Impact Of Insurance Expansion On Undiagnosed And Uncontrolled Chronic Conditions.
Policy makers have paid considerable attention to the financial implications of insurance expansion under the Affordable Care Act (ACA), but there is little evidence of the law's potential health effects. To gain insight into these effects, we analyzed data for 1999-2012 from the National Health and Nutrition Examination Survey to evaluate relationships between health insurance and the diagnosis and management of diabetes, hypercholesterolemia, and hypertension. People with insurance had significantly higher probabilities of diagnosis than matched uninsured people, by 14 percentage points for diabetes and hypercholesterolemia and 9 percentage points for hypertension. Among those with existing diagnoses, insurance was associated with significantly lower hemoglobin A1c (-0.58 percent), total cholesterol (-8.0 mg/dL), and systolic blood pressure (-2.9 mmHg). If the number of nonelderly Americans without health insurance were reduced by half, we estimate that there would be 1.5 million more people with a diagnosis of one or more of these chronic conditions and 659,000 fewer people with uncontrolled cases. Our findings suggest that the ACA could have significant effects on chronic disease identification and management, but policy makers need to consider the possible implications of those effects for the demand for health care services and spending for chronic disease.


Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks.
A principal task in dissecting the genetics of complex traits is to identify causal genes for disease phenotypes. We previously developed a method to infer causal relationships among genes through the integration of DNA variation, gene transcription and phenotypic information. Here we have validated our method through the characterization of transgenic and knockout mouse models of genes predicted to be causal for abdominal obesity. Perturbation of eight out of the nine genes, with Gas7, Me1 and Gpx3 being newly confirmed, resulted in significant changes in obesity-related traits. Liver expression signatures revealed alterations in common metabolic pathways and networks contributing to abdominal obesity and overlapped with a macrophage-enriched metabolic network module that is highly associated with metabolic traits in mice and humans. Integration of gene expression in the design and analysis of traditional F(2) intercross studies allows high-confidence prediction of causal genes and identification of pathways and networks involved.


Conceptual Combination in the LATL With and Without Syntactic Composition.
The relationship among syntactic, semantic, and conceptual processes in language comprehension is a central question to the neurobiology of language. Several studies have suggested that conceptual combination in particular can be localized to the left anterior temporal lobe (LATL), while syntactic processes are more often associated with the posterior temporal lobe or inferior frontal gyrus. However, LATL activity can also correlate with syntactic computations, particularly in narrative comprehension. Here we investigated the degree to which LATL conceptual combination is dependent on syntax, specifically asking whether rapid (∼200 ms) magnetoencephalography effects of conceptual combination in the LATL can occur in the absence of licit syntactic phrase closure and in the absence of a semantically plausible output for the composition. We find that such effects do occur: LATL effects of conceptual combination were observed even when there was no syntactic phrase closure or plausible meaning. But syntactic closure did have an additive effect such that LATL signals were the highest for expressions that composed both conceptually and syntactically. Our findings conform to an account in which LATL conceptual composition is influenced by local syntactic composition but is also able to operate without it.


Mixed higher-order anisotropic flow and nonlinear response coefficients of charged particles in PbPb collisions at s NN = 2.76 and 5.02 TeV.
Anisotropies in the initial energy density distribution of the quark-gluon plasma created in high energy heavy ion collisions lead to anisotropies in the azimuthal distributions of the final-state particles known as collective anisotropic flow. Fourier harmonic decomposition is used to quantify these anisotropies. The higher-order harmonics can be induced by the same order anisotropies (linear response) or by the combined influence of several lower order anisotropies (nonlinear response) in the initial state. The mixed higher-order anisotropic flow and nonlinear response coefficients of charged particles are measured as functions of transverse momentum and centrality in PbPb collisions at nucleon-nucleon center-of-mass energies s NN = 2.76 and 5.02 TeV with the CMS detector. The results are compared with viscous hydrodynamic calculations using several different initial conditions, as well as microscopic transport model calculations. None of the models provides a simultaneous description of the mixed higher-order flow harmonics and nonlinear response coefficients.


A clinical trial report of autologous bone marrow-derived mesenchymal stem cell transplantation in patients with spinal cord injury.
Spinal cord injury (SCI) is a severe neurological disease. An effective strategy for the treatment of SCI is urgently required. Stem cell transplantation has emerged as a viable therapeutic option with great potential for restoring neurological function lost following SCI. From 2009 to 2010, a total of 20 SCI patients were enrolled in a clinical trial by Wuhan Hongqiao Brain Hospital; all patients completed and signed informed consent prior to autologous bone marrow-derived mesenchymal stem cell transplantation. Analysis of subsequent treatment results indicated significant improvements in sensory, motor and autonomic nerve function as assessed by the American Spinal Injury Association's impairment scale. Thirty days after transplantation, a total of 15 patients (75%) demonstrated improvement, including four of the eight patients (50%) with grade A SCI, three of the four patients (75%) with grade B injury and all eight patients (100%) with grade C injury. The most common adverse events, fever and headache, disappeared within 24-48 h without treatment.


Blood pressure-associated polymorphism controls ARHGAP42 expression via serum response factor DNA binding.
We recently demonstrated that selective expression of the Rho GTPase-activating protein ARHGAP42 in smooth muscle cells (SMCs) controls blood pressure by inhibiting RhoA-dependent contractility, providing a mechanism for the blood pressure-associated locus within the ARHGAP42 gene. The goals of the current study were to identify polymorphisms that affect ARHGAP42 expression and to better assess ARHGAP42's role in the development of hypertension. Using DNase I hypersensitivity methods and ENCODE data, we have identified a regulatory element encompassing the ARHGAP42 SNP rs604723 that exhibits strong SMC-selective, allele-specific activity. Importantly, CRISPR/Cas9-mediated deletion of this element in cultured human SMCs markedly reduced endogenous ARHGAP42 expression. DNA binding and transcription assays demonstrated that the minor T allele variation at rs604723 increased the activity of this fragment by promoting serum response transcription factor binding to a cryptic cis-element. ARHGAP42 expression was increased by cell stretch and sphingosine 1-phosphate in a RhoA-dependent manner, and deletion of ARHGAP42 enhanced the progression of hypertension in mice treated with DOCA-salt. Our analysis of a well-characterized cohort of untreated borderline hypertensive patients suggested that ARHGAP42 genotype has important implications in regard to hypertension risk. Taken together, our data add insight into the genetic mechanisms that control blood pressure and provide a potential target for individualized antihypertensive therapies.


Glucosamine: an ingredient with skin and other benefits.
Both glucosamine and its derivative N-acetyl glucosamine are amino-monosaccharides that serve key biochemical functions on their own and as substrate precursors for the biosynthesis of polymers such as glycosaminoglycans (e.g., hyaluronic acid) and for the production of proteoglycans. Glucosamine has an excellent safety profile and has been shown to provide benefits in several clinical disorders. Glucosamine compounds have been reported to have several beneficial effects on the skin or skin cells. Because of its stimulation of hyaluronic acid synthesis, glucosamine has been shown to accelerate wound healing, improve skin hydration, and decrease wrinkles. In addition, as an inhibitor of tyrosinase activation, it inhibits melanin production and is useful in treatment of disorders of hyperpigmentation. Mechanistically, glucosamine also has both anti-inflammatory and chondroprotective effects. Clinical trials have shown benefit in using oral glucosamine supplementation to improve symptoms and slow the progression of osteoarthritis in humans. Glucosamine has also been used to prevent and treat osteoarthritis in animals. Based on other observations, glucosamine has been suggested for additional clinical uses, including treatment of inflammatory bowel disease, migraine headaches, and viral infections. The current clinical uses for topical and oral glucosamine compounds and the mechanistic rationale for these uses are reviewed here.


dKDM5/LID regulates H3K4me3 dynamics at the transcription-start site (TSS) of actively transcribed developmental genes.
H3K4me3 is a histone modification that accumulates at the transcription-start site (TSS) of active genes and is known to be important for transcription activation. The way in which H3K4me3 is regulated at TSS and the actual molecular basis of its contribution to transcription remain largely unanswered. To address these questions, we have analyzed the contribution of dKDM5/LID, the main H3K4me3 demethylase in Drosophila, to the regulation of the pattern of H3K4me3. ChIP-seq results show that, at developmental genes, dKDM5/LID localizes at TSS and regulates H3K4me3. dKDM5/LID target genes are highly transcribed and enriched in active RNApol II and H3K36me3, suggesting a positive contribution to transcription. Expression-profiling show that, though weakly, dKDM5/LID target genes are significantly downregulated upon dKDM5/LID depletion. Furthermore, dKDM5/LID depletion results in decreased RNApol II occupancy, particularly by the promoter-proximal Pol llo(ser5) form. Our results also show that ASH2, an evolutionarily conserved factor that locates at TSS and is required for H3K4me3, binds and positively regulates dKDM5/LID target genes. However, dKDM5/LID and ASH2 do not bind simultaneously and recognize different chromatin states, enriched in H3K4me3 and not, respectively. These results indicate that, at developmental genes, dKDM5/LID and ASH2 coordinately regulate H3K4me3 at TSS and that this dynamic regulation contributes to transcription.


Noise in biological circuits.
Noise biology focuses on the sources, processing, and biological consequences of the inherent stochastic fluctuations in molecular transitions or interactions that control cellular behavior. These fluctuations are especially pronounced in small systems where the magnitudes of the fluctuations approach or exceed the mean value of the molecular population. Noise biology is an essential component of nanomedicine where the communication of information is across a boundary that separates small synthetic and biological systems that are bound by their size to reside in environments of large fluctuations. Here we review the fundamentals of the computational, analytical, and experimental approaches to noise biology. We review results that show that the competition between the benefits of low noise and those of low population has resulted in the evolution of genetic system architectures that produce an uneven distribution of stochasticity across the molecular components of cells and, in some cases, use noise to drive biological function. We review the exact and approximate approaches to gene circuit noise analysis and simulation, and review many of the key experimental results obtained using flow cytometry and time-lapse fluorescent microscopy. In addition, we consider the probative value of noise with a discussion of using measured noise properties to elucidate the structure and function of the underlying gene circuit. We conclude with a discussion of the frontiers of and significant future challenges for noise biology.


TIGRFAMs and Genome Properties in 2013.
TIGRFAMs, available online at http://www.jcvi.org/tigrfams is a database of protein family definitions. Each entry features a seed alignment of trusted representative sequences, a hidden Markov model (HMM) built from that alignment, cutoff scores that let automated annotation pipelines decide which proteins are members, and annotations for transfer onto member proteins. Most TIGRFAMs models are designated equivalog, meaning they assign a specific name to proteins conserved in function from a common ancestral sequence. Models describing more functionally heterogeneous families are designated subfamily or domain, and assign less specific but more widely applicable annotations. The Genome Properties database, available at http://www.jcvi.org/genome-properties, specifies how computed evidence, including TIGRFAMs HMM results, should be used to judge whether an enzymatic pathway, a protein complex or another type of molecular subsystem is encoded in a genome. TIGRFAMs and Genome Properties content are developed in concert because subsystems reconstruction for large numbers of genomes guides selection of seed alignment sequences and cutoff values during protein family construction. Both databases specialize heavily in bacterial and archaeal subsystems. At present, 4284 models appear in TIGRFAMs, while 628 systems are described by Genome Properties. Content derives both from subsystem discovery work and from biocuration of the scientific literature.


Distribution and Severity of Myopic Maculopathy Among Highly Myopic Eyes.
The purpose of this study was to document the distribution of the severity of myopic maculopathy in a cohort of highly myopic patients and to explore the associated risk factors. A total of 890 Chinese highly myopes aged between 7 and 70 years (median age 19 years) and with spherical refraction -6.00 diopter (D) or worse in both eyes were investigated. All participants underwent detailed ophthalmic examination. Myopic maculopathy was graded into 5 categories according to the International Photographic Classification and Grading System using color fundus photographs: category 0, no myopic retinal lesions, category 1, tessellated fundus only; category 2, diffuse chorioretinal atrophy; category 3, patchy chorioretinal atrophy; category 4, macular atrophy. Category 2 or greater were further classified as clinically significant myopic maculopathy (CSMM). Data from 884 of 890 right eyes were available for analysis. The proportions of category 1, category 2, category 3, and category 4 were 20.0% (177 eyes), 20.2% (178 eyes), 2.6% (23 eyes), and 0.2% (2 eyes), respectively. The proportion of CSMM increased with more myopic refraction (odds ratio 1.57; 95% confidence interval: 1.46-1.68), longer axial length (odds ratio 2.97; 95% confidence interval: 2.50-3.53), and older age (40-70 years compared to 12-18 years, odds ratio 6.77; 95% confidence interval: 3.61-12.70). However, there was a higher proportion of CSMM in children aged 7 to 11 years than those aged 12 to 18 years (20.9% vs. 11.0%, P = 0.008). Older age, more myopic refraction, and longer axial length were associated with more severe myopic maculopathy. Although CSMM was uncommon among younger participants, children with early-onset high myopia have a disproportionately increased risk.


Triptolide Induces Cell Apoptosis by Targeting H3K4me3 and Downstream Effector Proteins in KM3 Multiple Myeloma Cells.
As the principal active ingredient in the Chinese herb Tripterygium wilfordii Hook.F (TwHF), triptolide has been shown to have very strong antitumor properties. The trimethylation of lysine 4 on histone H3 (H3K4me3) has been proposed to promote gene expression, and the accumulation of H3K4me3 at the transcriptional start sites of oncogenes is involved in carcinogenesis. To identify the association between the reduction of H3K4me3 and the apoptosis of MM cells induced by triptolide, we investigated the global patterns of H3K4me3 occupancy in the MM cell genome. Combined analyses using ChIP-on-chip and western blotting showed that H3K4me3 were highly enriched on the gene promoters of c-Myc and VEGFA and were associated with the up-regulation of both genes. Treatment of KM3 cells with triptolide and siRNA targeting ASH2L reduced the expression of c-Myc and VEGFA. These results suggest that triptolide can down-regulate c-Myc and VEGFA expression by blocking the accumulation of H3K4me3 on their promoters,and thus play an important role in anti-MM mechanism.


Development and characterization of monoclonal antibodies against Besnoitia besnoiti tachyzoites.
This is the first report on the development and characterization of eight monoclonal antibodies (MABs) generated against whole- and membrane-enriched tachyzoite extracts of the apicomplexan parasite Besnoitia besnoiti. Confocal laser scanning immunofluorescence microscopy was used to localize respective epitopes in B. besnoiti tachyzoites along the lytic cycle. A pattern compatible with dense granule staining was observed with MABs 2.A.12, 2.F.3 and 2.G.4, which could be confirmed by immunogold electron microscopy for MABs 2.A.12 and 2.F.3. In particular, MABs 2.F.3 and 2.G.4 were secreted during early invasion, proliferation and egress phases. MABs 3.10.8 and 5.5.11 labelled the tachyzoite surface, whilst MABs 1.17.8, 8.9.2 and 2.G.A recognized the apical tip, which is reminiscent for microneme localization. Besides, the epitopes recognized by the latter two (MABs 8.9.2 and 2.G.A) exhibited a redistribution from the anterior part across the parasite surface towards the posterior end during invasion. Most MABs developed were genus-specific. Indeed, the MABs cross-reacted neither with T. gondii nor with N. caninum tachyzoites. In summary, we have generated MABs that will be useful to study the key processes in the lytic cycle of the parasite and with additional promising diagnostic value. However, the molecular identity of the antigens recognized remains to be elucidated.


Straight talk: the challenge before modern day hinduism.
Hinduism, as an institution, offers very little to the poor and underprivileged within its fold. This is one of the prime reasons for voluntary conversion of Hindus from among its members. B.R. Ambedkar and A.R. Rahman provide poignant examples of how lack of education and health facilities for the underprivileged within its fold, respectively, led to their conversion. This can be countered by a movement to provide large-scale quality health [hospitals/PHCs] and educational [schools/colleges] facilities run by Hindu mission organisations spread over the cities and districts of India. A four point-four phase programmme is presented here to outline how this can be achieved. Those who have the genuine interests of Hinduism at heart will have to set such an agenda before them rather than strident and violent affirmations of its glories. One can understand the reasons for such stridency, but it is time it got converted into constructive affirmative action to keep the flock.


The circulatory-respiratory determination of death in organ donation.
Death statutes permit physicians to declare death on the basis of irreversible cessation of circulatory-respiratory or brain functions. The growing practice of organ donation after circulatory determination of death now requires physicians to exercise greater specificity in circulatory-respiratory death determination. We studied circulatory-respiratory death determination to clarify its concept, practice, and application to innovative circulatory determination of death protocols. It is ethically and legally appropriate to procure organs when permanent cessation (will not return) of circulation and respiration has occurred but before irreversible cessation (cannot return) has occurred because permanent cessation: 1) is an established medical practice standard for determining death; 2) is the meaning of "irreversible" in the Uniform Determination of Death Act; and 3) does not violate the "Dead Donor Rule." The use of unmodified extracorporeal membrane oxygenation in the circulatory determination of death donor after death is declared should be abandoned because, by restoring brain circulation, it retroactively negates the previous death determination. Modifications of extracorporeal membrane oxygenation that avoid this problem by excluding brain circulation are contrived, invasive, and, if used, should require consent of surrogates. Heart donation in circulatory determination of death is acceptable if proper standards are followed to declare donor death after establishing the permanent cessation of circulation. Pending additional data on "auto-resuscitation," we recommend that all circulatory determination of death programs should utilize the prevailing standard of 2 to 5 mins of demonstrated mechanical asystole before declaring death.


Consent for anaesthesia.
Current professional guidelines concerning information and consent for anaesthesia are a fair representation of English law. However, they reject the need for specific, written consent for anaesthesia, a position which is in accordance with other Western jurisdictions. This is understandable, as there would be a number of problems inherent in such an approach: the consent process would be unnecessarily labour and time intensive, the generic nature of the information to be disclosed would not allow for operator-dependent variables, and many of the disclosable risks continue to be of uncertain incidence. Moreover, written consent is not needed in order to defend cases of assault by anaesthetists. However, for the very reason that there are a large number of risks associated with anaesthesia (risks that are unknown to the majority of surgeons), together with the possibility of the courts moving towards a reasonable patient standard of information disclosure (as a result of the introduction of human rights legislation into English law), it is our view that the Association of Anaesthetists of Great Britain and Ireland should change their guidelines and advise anaesthetists to obtain separate, written affirmation from patients that certain risks and consequences of anaesthesia have been explained to them. In addition, a standardised consent form for anaesthesia may prove invaluable in retrospectively defending a claim of negligence founded around information disclosure, by recording exactly the risks and consequences of interventions discussed by the anaesthetist and the patient.


FcgammaRIII engagement provides activating signals to NKT cells in antibody-induced joint inflammation.
NKT cells promote antibody-induced arthritis, but the mechanism by which NKT cells are activated in this model remains unclear. It has been proposed that Fcgamma receptor (FcgammaR) contributes to NKT cell activation in antibody-induced arthritis. To address this issue, we explored the functions of FcgammaR on NKT cells in antibody-induced arthritis. RT-PCR and flow cytometric analysis demonstrated that NKT cells constitutively express surface FcgammaRIII but not FcgammaRI, -II, or -IV. FcgammaRIII engagement by aggregated IgG on NKT cells enhanced CD25 and CD69 expression, whereas FcgammaR(-/-) mouse NKT cells did not enhance activation. FcgammaRIII engagement on NKT cells enhanced the production of IL-4, IL-10, IL-13, and IFN-gamma, whereas FcgammaR-deficient NKT cells did not alter the production of these cytokines after aggregated IgG treatment. However, FcgammaR-deficient NKT cells were functionally intact in terms of TCR-induced activation. Moreover, adoptive transfer of FcgammaR-deficient NKT cells could not restore inflammation or TGF-beta production in the joint tissues of CD1d(-/-) mice, whereas adoptive transfer of wild-type NKT cells induced arthritis and reduced TGF-beta production in joint tissues. We conclude that FcgammaRIII engagement by IgG in joint tissues provides activating signals to NKT cells in antibody-induced arthritis.


Impact of a statewide home visiting program on parenting and on child health and development.
To assess the impact of a voluntary, paraprofessional home visiting program on promoting child health and development and maternal parenting knowledge, attitudes, and behaviors. This collaborative, experimental study of 6 Healthy Families Alaska (HFAK) programs enrolled 325 families from 1/00 to 7/01, randomly assigned them to HFAK and control groups, interviewed mothers at baseline, and followed families until children were 2 years old (85% follow-up). Child outcomes included health care use, development and behavior. Parent outcomes included knowledge of infant development, parenting attitudes, quality of the home environment, and parent-child interaction. HFAK records were reviewed to measure home visiting services. Home visitors were surveyed to measure knowledge, perceived effectiveness and perceived training adequacy. There was no overall impact on child health, but HFAK group children had more favorable developmental and behavioral outcomes. HFAK and control mothers had similar parenting outcomes except that HFAK mothers had greater parenting self-efficacy (35.1 vs. 34.6 based on the Teti Self-Efficacy Scale, p<.05). Fewer HFAK families had a poor home environment for learning (20% vs. 31%, p<.001). HFAK families were more likely to use center-based parenting services (48% vs. 39%, p<.05). The impact was greater for families with lower baseline risk (Family Stress Checklist scores<45). There was little evidence of efficacy for families with a higher dose of service. The program promoted child development and reduced problem behaviors at 2 years. Impact could be strengthened by improving home visitor effectiveness in promoting effective parenting. Future research is needed to determine whether short-term benefits are sustained.


Cord plasma concentrations of adiponectin and leptin in healthy term neonates: positive correlation with birthweight and neonatal adiposity.
Adiponectin is negatively associated with leptin, insulin and obesity in children and adults. Whereas increases in fetal insulin and leptin are associated with increased weight and adiposity at birth, the role of adiponectin in fetal growth has not yet been determined. The aims of this study were to examine the relationships between adiponectin and insulin, leptin, weight and adiposity at birth in healthy term infants. Anthropometric parameters including weight, length, circumferences and skinfold thickness were measured, and plasma lipid profiles, insulin, leptin and adiponectin concentrations in cord blood samples from 226 singleton infants born at term after uncomplicated pregnancies were assayed. Cord plasma adiponectin, leptin and insulin levels correlated significantly and positively with birthweight (P = 0.001, P < 0.001, P < 0.001, respectively) and the sum of skinfold thicknesses (P < 0.001, P < 0.001, P < 0.001, respectively). Mean cord plasma adiponectin and leptin levels, but not insulin level, were significantly higher in large-for-gestational-age (LGA) infants compared with appropriate-for-gestational-age (AGA) infants. Cord plasma leptin concentration, but not adiponectin concentration, was significantly higher in female infants than in male infants (P = 0.003 and P = 0.94, respectively). Cord plasma adiponectin concentration correlated positively with leptin level (P = 0.007) but not with insulin level (P = 0.78). High adiponectin levels are present in the cord blood. Cord plasma adiponectin and leptin levels are positively correlated with birthweight and adiposity. This suggests that adiponectin may be involved in regulating fetal growth.


Revision of Marphysa de Quatrefages, 1865 and some species of Nicidion Kinberg, 1865 with the erection of a new genus (Polychaeta: Eunicidae) from the Grand Caribbean.
Nine species of Marphysa from the Grand Caribbean Region are recognized and described based on the type and non-type specimens. One species is formally described as new: M. emiliae n. sp., and one is re-established as a valid species: M. fragilis Treadwell, 1911. The diagnosis of Nicidion Kinberg, 1865 is restricted based on novel features of the maxillary apparatus. Nicidion angeli (Carrera-Parra & Salazar-Vallejo, 1998) is redescribed, and two species that previously belonged to Marphysa, are transferred to Nicidion: N. longula (Ehlers, 1887) n. comb. and N. obtusa (Verrill, 1900) n. comb.. A new genus Treadwellphysa n. gen. is proposed to include those species having a newly described type of chaetae named spinifalcigers (exhibiting a mixture of falciger and spiniger blades), the base of maxillae II with a small elevation, and the ventral cirri with swollen base as transverse welt with short digitiform tip. Treadwellphysa n. gen. includes a new species, T. yucatanensis n. sp. and three other species previously included in Marphysa: T. amadae (Fauchald, 1977) n. comb., T. languida (Treadwell, 1921) n. comb., and T. veracruzensis (de León-González & Díaz-Castañeda, 2006) n. comb. Some morphological features are evaluated to clarify their variability with respect to specimen size. A key to Eunicidae genera, and keys to species of Marphysa and Treadwellphysa n. gen. from the Grand Caribbean region are given.