Oncogenic KIT mutations induce STAT3-dependent autophagy to support cell proliferation in acute myeloid leukemia.
Autophagy is associated with both survival and cell death in myeloid malignancies. Therefore, deciphering its role in different genetically defined subtypes of acute myeloid leukemia (AML) is critical. Activating mutations of the KIT receptor tyrosine kinase are frequently detected in core-binding factor AML and are associated with a greater risk of relapse. Herein, we report that basal autophagy was significantly increased by the KITD816V mutation in AML cells and contributed to support their cell proliferation and survival. Invalidation of the key autophagy protein Atg12 strongly reduced tumor burden and improved survival of immunocompromised NSG mice engrafted with KITD816V TF-1 cells. Downstream of KITD816V, STAT3, but not AKT or ERK pathways, was identified as a major regulator of autophagy. Accordingly, STAT3 pharmacological inhibition or downregulation inhibited autophagy and reduced tumor growth both in vitro and in vivo. Taken together, our results support the notion that targeting autophagy or STAT3 opens up an exploratory pathway for finding new therapeutic opportunities for patients with CBF-AML or others malignancies with KITD816V mutations.


Multilayer perceptrons: approximation order and necessary number of hidden units.
This paper considers the approximation of sufficiently smooth multivariable functions with a multilayer perceptron (MLP). For a given approximation order, explicit formulas for the necessary number of hidden units and its distributions to the hidden layers of the MLP are derived. These formulas depend only on the number of input variables and on the desired approximation order. The concept of approximation order encompasses Kolmogorov-Gabor polynomials or discrete Volterra series, which are widely used in static and dynamic models of nonlinear systems. The results are obtained by considering structural properties of the Taylor polynomials of the function in question and of the MLP function.


Copper promoted N-alkylation of sulfoximines with alkylboronic acid under mild conditions.
The copper meditated N-methylation of sulfoximines using methylboronic acid is reported. The reactions provide excellent yields in a short span of time under mild conditions. The optimized conditions were also found to be suitable for the N-alkylation of sulfoximine with different alkylboronic acids. In addition, N-methylation and cyclopropylation of the bioactive l-methionine sulfoximine derivative was demonstrated under standard reaction conditions.


Neural Signatures of Spatial Statistical Learning: Characterizing the Extraction of Structure from Complex Visual Scenes.
Behavioral evidence has shown that humans automatically develop internal representations adapted to the temporal and spatial statistics of the environment. Building on prior fMRI studies that have focused on statistical learning of temporal sequences, we investigated the neural substrates and mechanisms underlying statistical learning from scenes with a structured spatial layout. Our goals were twofold: (1) to determine discrete brain regions in which degree of learning (i.e., behavioral performance) was a significant predictor of neural activity during acquisition of spatial regularities and (2) to examine how connectivity between this set of areas and the rest of the brain changed over the course of learning. Univariate activity analyses indicated a diffuse set of dorsal striatal and occipitoparietal activations correlated with individual differences in participants' ability to acquire the underlying spatial structure of the scenes. In addition, bilateral medial-temporal activation was linked to participants' behavioral performance, suggesting that spatial statistical learning recruits additional resources from the limbic system. Connectivity analyses examined, across the time course of learning, psychophysiological interactions with peak regions defined by the initial univariate analysis. Generally, we find that task-based connectivity with these regions was significantly greater in early relative to later periods of learning. Moreover, in certain cases, decreased task-based connectivity between time points was predicted by overall posttest performance. Results suggest a narrowing mechanism whereby the brain, confronted with a novel structured environment, initially boosts overall functional integration and then reduces interregional coupling over time.


How solvent controls electronic energy transfer and light harvesting: toward a quantum-mechanical description of reaction field and screening effects.
This paper presents a quantum-mechanical study of electronic energy transfer (EET) coupling on over 100 pairs of chromophores taken from photosynthetic light-harvesting antenna proteins. Solvation effects due to the protein, intrinsic waters, and surrounding medium are analyzed in terms of screening and reaction field contributions using a model developed recently that combines a linear response approach with the polarizable continuum model (PCM). We find that the screening of EET interactions is quite insensitive to the quantum-mechanical treatment adopted. In contrast, it is greatly dependent on the geometrical details (distance, shape, and orientation) of the chromophore pair considered. We demonstrate that implicit (reaction field) as well as screening effects are dictated mainly by the optical dielectric properties of the host medium, while the effect of the static properties is substantially less important. The empirical distance-dependent screening function we proposed in a recent letter (Scholes, G. D.; Curutchet, C.; Mennucci, B.; Cammi, R.; Tomasi, J. J. Phys. Chem. B 2007, 111, 6978-6982) is analyzed and compared to other commonly used screening factors. In addition, we show that implicit medium effects on the coupling, resulting from changes in the transition densities upon solvation, are strongly dependent on the particular system considered, thus preventing the possibility of defining a general empirical expression for such an effect.


Diffractive optical elements as raster-image generators.
The use of diffractive optical elements (DOEs) to generate complex raster images for a primarily artistic purpose is dealt with. Aspects of human vision that are relevant for the design of such elements are discussed. A design method based on an iterative Fourier transform algorithm and extended with elements from the direct-binary-search and the simulated-annealing algorithms is described. The proposed method provides a large set of parameters that can be adjusted freely to optimize it for any given design task. For demonstration a phase-only DOE was designed that generates an image of a Chinese dragon as a diffraction pattern. It was realized as a surface-relief element on a planar substrate through multilevel binary lithography and reactive-ion etching. Experimental tests confirm the usefulness of the design and the fabrication procedures to achieve excellent image quality.


Heterozygous mutations cause genetic instability in a yeast model of cancer evolution.
Genetic instability, a heritable increase in the rate of genetic mutation, accelerates evolutionary adaptation1 and is widespread in cancer2,3. In mammals, instability can arise from damage to both copies of genes involved in DNA metabolism and cell cycle regulation4 or from inactivation of one copy of a gene whose product is present in limiting amounts (haploinsufficiency5); however, it has proved difficult to determine the relative importance of these two mechanisms. In Escherichia coli6, the application of repeated, strong selection enriches for genetic instability. Here we have used this approach to evolve genetic instability in diploid cells of the budding yeast Saccharomyces cerevisiae, and have isolated clones with increased rates of point mutation, mitotic recombination, and chromosome loss. We identified candidate, heterozygous, instability-causing mutations; engineering these mutations, as heterozygotes, into the ancestral diploid strain caused genetic instability. Mutations that inactivated one copy of haploinsufficient genes were more common than those that dominantly altered the function of the mutated gene copy. The mutated genes were enriched for genes functioning in transport, protein quality control, and DNA metabolism, and have revealed new targets for genetic instability7-11, including essential genes. Although only a minority (10 out of 57 genes with orthologues or close homologues) of the targets we identified have homologous human genes that have been implicated in cancer2, the remainder are candidates to contribute to human genetic instability. To test this hypothesis, we inactivated six examples in a near-haploid human cell line; five of these mutations increased instability. We conclude that single genetic events cause genetic instability in diploid yeast cells, and propose that similar, heterozygous mutations in mammalian homologues initiate genetic instability in cancer.


Correlates of body dissatisfaction among Taiwanese adolescents.
This study was designed to explore factors associated with body dissatisfaction among Taiwanese adolescents. Participants were randomly selected from five high schools in Taipei County, Taiwan. A total sample of 883 adolescents aged 12-16 was included. Body mass index (BMI) was calculated using self-reported weight and height. The Contour Drawing Rating Scale was used to assess body dissatisfaction. Other measurements included the Multidimensional Body-Self Relations Questionnaire-Appearance Evaluation (MBSRQ-AE), the Rosenberg Self-esteem Scale, the Eating Disorder Inventory-Perfectionism, the Socio-cultural Attitudes Towards Appearance Questionnaire (SATAQ-Internalization and SATAQ-Awareness), and physical activity. Multiple linear regression analyses were performed separately by gender to examine predictors of body dissatisfaction. girls reported significantly higher body dissatisfaction, awareness of the socio-cultural ideals (SATAQ-Awareness), as well as the internalization of those ideals (SATAQ-Internalization) and lower satisfaction with their physical appearance (MBSRQ-AE). This indicated that girls felt less positive with their overall appearance and had a higher level of recognition and endorsement of the social standards of appearance than boys. Satisfaction with physical appearance (MBSRQ-AE), BMI and internalization of socio-cultural ideals (SATAQ-Internalization) were unique predictors of body dissatisfaction for both genders. this study enhanced the understanding about body dissatisfaction in Eastern populations. Perceived physical appearance, BMI and internalization of the socio-cultural ideals predicted body dissatisfaction, which are evident in Taiwan, as well as in Western based research. However, these factors only explained a small variance in body dissatisfaction for boys, suggesting a need in identifying more factors related to body dissatisfaction among boys.


Population pharmacokinetics of mycophenolic acid : a comparison between enteric-coated mycophenolate sodium and mycophenolate mofetil in renal transplant recipients.
The pharmacokinetics of mycophenolic acid (MPA) were compared in renal transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS). MPA concentration-time profiles were included from EC-MPS- (n = 208) and MMF-treated (n = 184) patients 4-257 months after renal transplantation. Population pharmacokinetic analysis was performed using nonlinear mixed-effects modelling (NONMEM). A two-compartment model with first-order absorption and elimination was used to describe the data. No differences were detected in MPA clearance, intercompartmental clearance, or the central or peripheral volume of distribution. Respective values and interindividual variability (IIV) were 16 L/h (39%), 22 L/h (78%), 40 L (100%) and 518 L (490%). EC-MPS was absorbed more slowly than MMF with respective absorption rate constant values of 3.0 h(-1) and 4.1 h(-1) (p < 0.001) [IIV 187%]. A mixture model was used for the change-point parameter lag-time (t(lag)) in order to describe IIV in this parameter adequately for EC-MPS. Following the morning dose of EC-MPS, the t(lag) values were 0.95, 1.88 and 4.83 h for 51%, 32% and 17% of the population (IIV 8%), respectively. The morning t(lag) following EC-MPS administration was significantly different from both the t(lag) following MMF administration (0.30 h; p < 0.001 [IIV 11%]) and the t(lag) following the evening dose of EC-MPS (9.04 h; p < 0.001 [IIV 40%]). Post hoc analysis showed that the t(lag) was longer and more variable following EC-MPS administration (morning median 2.0 h [0.9-5.5 h], evening median 8.9 h [5.4-12.3 h]) than following MMF administration (median 0.30 h [0.26-0.34 h]; p < 0.001). The morning MPA predose concentrations were higher and more variable following EC-MPS administration than following MMF administration, with respective values of 2.6 mg/L (0.4-24.4 mg/L) and 1.6 mg/L (0.2-7.6 mg/L). The correlation between predose concentrations and the area under the plasma concentration-time curve (AUC) was lower in EC-MPS-treated patients (r(2) = 0.02) than in MMF-treated patients (r(2) = 0.48). Absorption of MPA was delayed and also slower following EC-MPS administration than following MMF administration. Furthermore, the t(lag) varied more in EC-MPS-treated patients. MPA predose concentrations were poorly correlated with the MPA AUC in both MMF- and EC-MPS-treated patients.


Consequences to water suppliers of collecting rainwater on housing estates.
The collection, storage and use of rainwater from roofs reduce the need for potable water. However, if water suppliers are to decrease their infrastructure costs as well as their operational costs (due to water savings), the rainwater system has to provide most of the time a significant percentage of the water demand. This paper adopts the viewpoint of the water suppliers and investigates how reliable this source of water is in the case of a housing estate, considering WC flushing as the only water demand. A housing estate was modelled and different realistic input scenarios (water demand for WC flushing, storage capacity, roof area, and rainfall) were defined. Three indicators were exhibited. The variability generated by each input on the indicators was evaluated. The indicators were estimated for 63 homogeneously distributed French cities. Among the indicators exhibited in this paper, the most relevant one is the percentage of water supplied from the tank that is secured during 95% of the days of the simulation. The main conclusion is that the optimum way of determining the storage capacity of the rainwater collection system is not the same from the viewpoint of the users than from the viewpoint of the water suppliers. Indeed, water suppliers tend to require bigger tanks in order to take into account the rainwater collection systems in their management plan.


Stress, hippocampal plasticity, and spatial learning.
During the last two decades numerous studies have been conducted in an attempt to correlate the mechanisms of long-term potentiation (LTP) of hippocampal synaptic transmission with those required for spatial memory formation in the hippocampus. Because stressful events block the induction of hippocampal LTP, it has been suggested that deficits in spatial learning following stress may be related to suppression of LTP-like phenomena in the hippocampus. Here I review these studies and discuss them in light of the emerging view that stress may induce changes in thresholds for synaptic plasticity necessary for both LTP induction and spatial memory formation. This phenomenon, known as metaplasticity, may involve a glucocorticoid modulation of calcium homeostasis.


Atomic structure and electronic properties of A2B2XY (A = Si-Pb, B = Cl-I, and XY = PN and SiS) inorganic double helices: first principles calculations.
We study the structural stability and electronic properties of new classes of DNA-like inorganic double helices of the type A2B2XY (A = Si-Pb, B = Cl-I, and XY = PN and SiS) by employing first principles density functional theory (DFT) calculations including van der Waals interactions. In these quaternary double helices PN or SiS forms the inner helix while the AB helix wraps around the inner helix and the two are interconnected. We find that the bromides and iodides of Ge, Sn, and Pb as well as Pb2Cl2PN form structurally stable double helices while Ge2I2SiS as well as bromides and iodides of Sn and Pb have stable double helices. The atomic structures of different double helices have been analyzed in detail to understand the stability of these systems as there is up to about 80% difference in the interatomic distances in the two helices which is remarkable. Also in these new classes of double helices there is polar covalent bonding in the inner helix due to heteroatoms. We have calculated the DDEC6 partial atomic charges and bond orders which suggest strong covalent bonding in the inner helix. The electronic structure reveals that these double helices are semiconducting and in many cases the band gap is direct. Furthermore, we have studied the effects of doping and found that hole doping is the most appropriate way to tuning their electronic properties.


The Phase-Shifting Effect of Bright Light Exposure on Circadian Rhythmicity in the Human Transcriptome.
Light is a potent synchronizer of the central circadian clock; however, the effect of light exposure on peripheral gene expression is largely unknown. The objective of this study was to explore the effect of bright light exposure on genome-wide peripheral gene expression levels during a 4-day simulated night shift protocol in which the habitual sleep period is delayed by 10 h. Eleven healthy participants (mean age, 24 years; range, 18-30; 10 men/1 woman) were studied under controlled laboratory conditions. Three participants were exposed to bright light (~6,500 lux) for 8 h during the nightly waking period, while the other 8 were maintained in dim-light conditions (~10 lux). At baseline and on the fourth day after the shift in the sleep period, blood samples were collected during two 24-h measurement periods. RNA was extracted from peripheral blood mononuclear cells (PBMCs) and used to obtain transcriptomic data. Using 2 independent approaches to determine phase shifts among rhythmically expressed genes after the shifted sleep schedule compared with baseline, we found that the average phase delay in the bright light group was approximately 8 to 9 h, whereas the average phase delay in the control group was approximately 1 to 2 h, both at the group level and at the individual level. In line with these findings, further analysis using partial least squares regression indicated that the peripheral circadian transcriptome of PBMCs was predictive of the phase of the central circadian pacemaker after only 3 days of bright light exposure. These results indicate that bright light exposure exerts a phase-shifting effect on the circadian transcriptome in PBMCs with a magnitude similar to its effect on the central circadian clock.


Haplotype Association Mapping Identifies a Candidate Gene Region in Mice Infected With Staphylococcus aureus.
Exposure to Staphylococcus aureus has a variety of outcomes, from asymptomatic colonization to fatal infection. Strong evidence suggests that host genetics play an important role in susceptibility, but the specific host genetic factors involved are not known. The availability of genome-wide single nucleotide polymorphism (SNP) data for inbred Mus musculus strains means that haplotype association mapping can be used to identify candidate susceptibility genes. We applied haplotype association mapping to Perlegen SNP data and kidney bacterial counts from Staphylococcus aureus-infected mice from 13 inbred strains and detected an associated block on chromosome 7. Strong experimental evidence supports the result: a separate study demonstrated the presence of a susceptibility locus on chromosome 7 using consomic mice. The associated block contains no genes, but lies within the gene cluster of the 26-member extended kallikrein gene family, whose members have well-recognized roles in the generation of antimicrobial peptides and the regulation of inflammation. Efficient mixed-model association (EMMA) testing of all SNPs with two alleles and located within the gene cluster boundaries finds two significant associations: one of the three polymorphisms defining the associated block and one in the gene closest to the block, Klk1b11. In addition, we find that 7 of the 26 kallikrein genes are differentially expressed between susceptible and resistant mice, including the Klk1b11 gene. These genes represent a promising set of candidate genes influencing susceptibility to Staphylococcus aureus.


Nonribosomal peptide synthetase genes pesL and pes1 are essential for Fumigaclavine C production in Aspergillus fumigatus.
The identity of metabolites encoded by the majority of nonribosomal peptide synthetases in the opportunistic pathogen, Aspergillus fumigatus, remains outstanding. We found that the nonribosomal peptide (NRP) synthetases PesL and Pes1 were essential for fumigaclavine C biosynthesis, the end product of the complex ergot alkaloid (EA) pathway in A. fumigatus. Deletion of either pesL (ΔpesL) or pes1 (Δpes1) resulted in complete loss of fumigaclavine C biosynthesis, relatively increased production of fumitremorgins such as TR-2, fumitremorgin C and verruculogen, increased sensitivity to H(2)O(2), and increased sensitivity to the antifungals, voriconazole, and amphotericin B. Deletion of pesL resulted in severely reduced virulence in an invertebrate infection model (P < 0.001). These findings indicate that NRP synthesis plays an essential role in mediating the final prenylation step of the EA pathway, despite the apparent absence of NRP synthetases in the proposed EA biosynthetic cluster for A. fumigatus. Liquid chromatography/diode array detection/mass spectrometry analysis also revealed the presence of fumiquinazolines A to F in both A. fumigatus wild-type and ΔpesL strains. This observation suggests that alternative NRP synthetases can also function in fumiquinazoline biosynthesis, since PesL has been shown to mediate fumiquinazoline biosynthesis in vitro. Furthermore, we provide here the first direct link between EA biosynthesis and virulence, in agreement with the observed toxicity associated with EA exposure. Finally, we demonstrate a possible cluster cross-talk phenomenon, a theme which is beginning to emerge in the literature.


Obstructive sleep apnea (OSA) and driving safety.
Intermittent hypoxia and sleep fragmentation cause excessive daytime sleepiness (EDS) and cognitive impairment in obstructive sleep apnoea (OSA); neuroimaging and neurophysiological studies in patients with OSA have delineated a putative regional "fingerprint" of OSA-induced brain injury: a disconnection of the fronto-parietal regions and a disruption of the thalamocortical oscillator, with involvement of the hippocampal formation with impaired attention, awareness, working memory, time reaction, visuoconstructive and executive functions. For these reasons OSA is the main medical cause of EDS and is also associated with an increased risk of motor vehicle accidents (MVAs). About 7% of MVAs for a population of male drivers involved in MVAs are attributable to OSA. Subjects with OSA have nearly twofold increased odds of work accidents. Professional drivers add fatigue to sleep deprivation. A higher risk of MVAs cannot be adequately explained by OSA and sleep deprivation (SD), and EDS is a further, independent risk factor like the other two. There is an association between the amount of hours of sleep per night and MVA or near miss accidents (NMA) rates with an inverse linear correlation. When OSA, SD or EDS are present, the risk of MVAs or NMAs in truck drivers is severely increased. Taking a rest break or a nap appear to be protective against MVAs e NMAs and they should be considered a primary prevention strategy together with screening for OSA, EDS, and SD.


Arbitrary protein-protein docking targets biologically relevant interfaces.
Protein-protein recognition is of fundamental importance in the vast majority of biological processes. However, it has already been demonstrated that it is very hard to distinguish true complexes from false complexes in so-called cross-docking experiments, where binary protein complexes are separated and the isolated proteins are all docked against each other and scored. Does this result, at least in part, reflect a physical reality? False complexes could reflect possible nonspecific or weak associations. In this paper, we investigate the twilight zone of protein-protein interactions, building on an interesting outcome of cross-docking experiments: false complexes seem to favor residues from the true interaction site, suggesting that randomly chosen partners dock in a non-random fashion on protein surfaces. Here, we carry out arbitrary docking of a non-redundant data set of 198 proteins, with more than 300 randomly chosen "probe" proteins. We investigate the tendency of arbitrary partners to aggregate at localized regions of the protein surfaces, the shape and compositional bias of the generated interfaces, and the potential of this property to predict biologically relevant binding sites. We show that the non-random localization of arbitrary partners after protein-protein docking is a generic feature of protein structures. The interfaces generated in this way are not systematically planar or curved, but tend to be closer than average to the center of the proteins. These results can be used to predict biological interfaces with an AUC value up to 0.69 alone, and 0.72 when used in combination with evolutionary information. An appropriate choice of random partners and number of docking models make this method computationally practical. It is also noted that nonspecific interfaces can point to alternate interaction sites in the case of proteins with multiple interfaces. We illustrate the usefulness of arbitrary docking using PEBP (Phosphatidylethanolamine binding protein), a kinase inhibitor with multiple partners. An approach using arbitrary docking, and based solely on physical properties, can successfully identify biologically pertinent protein interfaces.


Biomedical informatics advancing the national health agenda: the AMIA 2015 year-in-review in clinical and consumer informatics.
The field of biomedical informatics experienced a productive 2015 in terms of research. In order to highlight the accomplishments of that research, elicit trends, and identify shortcomings at a macro level, a 19-person team conducted an extensive review of the literature in clinical and consumer informatics. The result of this process included a year-in-review presentation at the American Medical Informatics Association Annual Symposium and a written report (see supplemental data). Key findings are detailed in the report and summarized here. This article organizes the clinical and consumer health informatics research from 2015 under 3 themes: the electronic health record (EHR), the learning health system (LHS), and consumer engagement. Key findings include the following: (1) There are significant advances in establishing policies for EHR feature implementation, but increased interoperability is necessary for these to gain traction. (2) Decision support systems improve practice behaviors, but evidence of their impact on clinical outcomes is still lacking. (3) Progress in natural language processing (NLP) suggests that we are approaching but have not yet achieved truly interactive NLP systems. (4) Prediction models are becoming more robust but remain hampered by the lack of interoperable clinical data records. (5) Consumers can and will use mobile applications for improved engagement, yet EHR integration remains elusive.


New insights into the anticancer activity of carnosol: p53 reactivation in the U87MG human glioblastoma cell line.
Glioblastoma multiforme (GBM) is an aggressive brain tumour with high resistance to radio- and chemotherapy. As such, increasing attention has focused on developing new therapeutic strategies to improve treatment responses. Recently, attention has been shifted to natural compounds that are able to halt tumour development. Among them, carnosol (CAR), a phenolic diterpene present in rosemary, has become a promising molecule that is able to prevent certain types of solid cancer. However, no data are available on the effects of CAR in GBM. Here, CAR activity decreased the proliferation of different human glioblastoma cell lines, particularly cells that express wild type p53. The p53 pathway is involved in the control of apoptosis and is often impaired in GBM. Notably, CAR, through the dissociation of p53 from its endogenous inhibitor MDM2, was able to increase the intracellular p53 levels in GBM cells. Accordingly, functional reactivation of p53 was demonstrated by the stimulation of p53 target genes' transcription, the induction of apoptosis and cell cycle blockade. Most importantly, CAR produced synergistic effects with temozolomide (TMZ) and reduced the restoration of the tumour cells' proliferation after drug removal. Thus, for the first time, these data highlighted the potential use of the diterpene in the sensitization of GBM cells to chemotherapy through a direct re-activation of p53 pathway. Furthermore, progress has been made in delineating the biochemical mechanisms underlying the pro-apoptotic effects of this molecule.


Reconstructing Late Pleistocene paleoclimate at the scale of human behavior: an example from the Neandertal occupation of La Ferrassie (France).
Exploring the role of changing climates in human evolution is currently impeded by a scarcity of climatic information at the same temporal scale as the human behaviors documented in archaeological sites. This is mainly caused by high uncertainties in the chronometric dates used to correlate long-term climatic records with archaeological deposits. One solution is to generate climatic data directly from archaeological materials representing human behavior. Here we use oxygen isotope measurements of Bos/Bison tooth enamel to reconstruct summer and winter temperatures in the Late Pleistocene when Neandertals were using the site of La Ferrassie. Our results indicate that, despite the generally cold conditions of the broader period and despite direct evidence for cold features in certain sediments at the site, Neandertals used the site predominantly when climatic conditions were mild, similar to conditions in modern day France. We suggest that due to millennial scale climate variability, the periods of human activity and their climatic characteristics may not be representative of average conditions inferred from chronological correlations with long-term climatic records. These results highlight the importance of using direct routes, such as the high-resolution archives in tooth enamel from anthropogenically accumulated faunal assemblages, to establish climatic conditions at a human scale.


Indigenous perspectives on education for sustainable healthcare.
A range of global environmental changes are contributing to an increasing global burden of disease. Since human health and well-being are intimately associated with the health of our planet, healthcare providers will not only be charged with caring for this expanding disease burden but will also need to become more environmentally sustainable in their professional practice. There is thus an urgent need in the health professions education community to prioritize environmentally sustainable healthcare practice, which must include and prioritize Indigenous voices and Indigenous knowledge systems. Critical global dialogue on the significance of Indigenous knowledge systems in educating health professionals for a sustainable future will be required if we are ready to ensure the generations that follow us are able to live healthy lives. Indigenous ways of 'being' in the world, which emphasize the importance of interconnection and reciprocal stewardship with everything in the natural world, are essential for advancing education for sustainable healthcare and overall well-being. Given the colonial legacy however, Indigenous people, despite their essential knowledge systems and abilities, still face many barriers accessing safe decolonizing spaces and presence in health professions education, which needs to be addressed.


Multicenter randomized controlled trial on Duration of Therapy for Thrombosis in Children and Young Adults (the Kids-DOTT trial): pilot/feasibility phase findings.
Randomized controlled trials (RCTs) on pediatric venous thromboembolism (VTE) treatment have been challenged by unsubstantiated design assumptions and/or poor accrual. Pilot/feasibility (P/F) studies are critical to future RCT success. The Kids-DOTT trial is a multicenter RCT investigating non-inferiority of a 6-week (shortened) versus 3-month (conventional) duration of anticoagulation in patients aged < 21 years with provoked venous thrombosis. Primary efficacy and safety endpoints are symptomatic recurrent VTE at 1 year and anticoagulant-related, clinically relevant bleeding. In the P/F phase, 100 participants were enrolled in an open, blinded-endpoint, parallel-cohort RCT design. No eligibility violations or randomization errors occurred. Of the enrolled patients, 69% were randomized, 3% missed the randomization window, and 28% were followed in prespecified observational cohorts for completely occlusive thrombosis or persistent antiphospholipid antibodies. Retention at 1 year was 82%. Interobserver agreement between local and blinded central determination of venous occlusion by imaging at 6 weeks after diagnosis was strong (k-statistic = 0.75; 95% confidence interval [CI] 0.48-1.0). The primary efficacy and safety event rates were 3.3% (95% CI 0.3-11.5%) and 1.4% (95% CI 0.03-7.4%). The P/F phase of the Kids-DOTT trial has demonstrated the validity of vascular imaging findings of occlusion as a randomization criterion, and defined randomization, retention and endpoint rates to inform the fully powered RCT.


Serotonin modulates the excitatory synaptic transmission in the dentate granule cells.
Serotonergic fibers from the raphe nuclei project to the hippocampal formation, the activity of which is known to modulate the inhibitory interneurons in the dentate gyrus. On the other hand, serotonergic modulation of the excitatory synapses in the dentate gyrus is not well examined. In the present study, we examined the effects of 5-HT on the excitatory postsynaptic potentials (EPSPs) in the dentate granule cells evoked by the selective stimulation of the lateral perforant path (LPP), the medial perforant path (MPP), or the mossy cell fibers (MCF). 5-HT depressed the amplitude of unitary EPSPs (uEPSPs) evoked by the stimulation of LPP or MPP, whereas uEPSPs evoked by MCF stimulation were little affected. The effect was partly explained by the decrease of the resting membrane resistance following the activation of 5-HT1A receptors, which was confirmed by computer simulations. We also found that the probability of evoking uEPSP by LPP stimulation but not MPP or MCF stimulation was reduced by 5-HT and that the paired-pulse ratio of LPP-evoked EPSP but not that of MPP- or MCF-evoked ones was increased by 5-HT. These effects were blocked by 5-HT2 antagonist, suggesting that the transmitter release in the LPP-granule cell synapse is inhibited by the activation of 5-HT2 receptors. The present results suggest that 5-HT can modulate the EPSPs in the dentate granule cells by at least two distinct mechanisms.


Comparison of Outcome and Quality of Life Between Thulium Laser (VelaTM XL) Enucleation of Prostate and Bipolar Transurethral Enucleation of the Prostate (B-TUEP).
In this study, we compared patient outcomes between the 120-W thulium laser (Vela™XL) prostate enucleation (ThuLEP) and bipolar transurethral enucleation of the prostate (B-TUEP) techniques. We excluded patients with concomitant prostate cancer and bladder cancer and prospectively analyzed patients with benign prostatic obstruction (BPO) who underwent ThuLEP and B-TUEP from October 2018 to January 2021 in our institution. Patients' demographics, comorbidities, prostate volumes, prostate-specific antigen (PSA) levels, and International Prostate Symptoms Score (IPSS) were recorded. Perioperative outcomes including intraoperative blood loss, prostate resection percentage of the transition zone, postoperative pain score (numeric rating scale, NRS), complications, changes in postoperative uroflowmetry parameters, IPSS, and the rate of reuse of BPH medications were also evaluated. The data of a total of 111 patients (ThuLEP: 49, B-TUEP: 62) met the inclusion criteria were collected and analyzed prospectively. Our results revealed no significant differences between ThuLEP and B-TUEP in terms of operation time, prostate tissue enucleated, and days of hospitalization. However, patients in the ThuLEP group reported less pain after surgery than those in the B-TUEP group, and a higher proportion of patients in the B-TUEP group returned to the emergency department due to complications within one month postoperatively, with hematuria being the main cause. No significant differences were observed between the groups in changes in uroflowmetry parameters and IPSS at 2 weeks, 3 months, and 6 months postoperatively. The efficacy of ThuLEP was comparable to that of B-TUEP in terms of maximal flow rate, voiding volume, IPSS, and quality of life. ThuLEP also had several advantages over B-TUEP, including less blood loss and less postoperative pain. Therefore, ThuLEP can be considered a treatment of choice for BPH/bladder outlet obstruction, specifically for patients with a bleeding tendency and fear of pain.


Elevated systemic neutrophil count in diabetic retinopathy and diabetes: a hospital-based cross-sectional study of 30,793 Korean subjects.
To evaluate the association between systemic parameters including inflammatory markers and diabetic retinopathy (DR). This was a cross-sectional study enrolling 30,793 persons who visited a health care center for a medical checkup. Diabetic patients were classified into five DR groups: no DR; mild, moderate, or severe nonproliferative DR, and proliferative DR. A full laboratory workup and comprehensive medical data on the subjects were obtained and used for analysis. The mean (SD) age of the participants was 47.4 (11.9) years (range, 18-90) and the male-to-female ratio was 55.7:44.3. The prevalence of diabetes and DR were 6.6% (2,020/30,793) and 5.3% (108/2,020), respectively. Among inflammatory markers, the mean absolute neutrophil count (ANC; per microliter) was significantly higher in the DR than in the non-DR group (3900 vs. 3566; P = 0.0143) and in diabetic than in nondiabetic subjects (3583 vs. 3262; P < 0.0001). Subjects in the fourth quintiles of ANC showed 2.7 odds of having DR by multivariate analysis, and there was a linear trend in the odds ratios according to increasing ANC levels. The level of ANC and the ANC/leukocyte ratio also demonstrated a linearly increasing trend with the severity of DR, even after adjustment for other clinical factors, including HbA1c. Among significant risk factors of DR, ANC showed the second strongest predictive power for DR (AUROC = 0.590) after HbA1C (0.624). Elevated systemic neutrophil count is associated with the presence and severity of DR as well as diabetes. This result indicates that systemic subclinical inflammation is related with DR, and neutrophil-mediated inflammation may play an important role in the pathogenesis of DR.


First Report of Frog Skin Disease in Cassava (Manihot esculenta) in Venezuela.
Frogskin disease (FSD) is a disease of clonally propagated cassava (Manihot esculenta Crantz) and has been reported to reduce cassava yields significantly in South America (1). FSD is caused by an uncharacterized virus that is restricted to South America. The evidence indicates FSD is transmitted by stem cuttings and graft (3). However, little information is available on its distribution and incidence in Venezuela. Eighty-seven samples with virus-like symptoms were collected with the help of technical staff and producers in cassava-producing states: Amazonas (1 sample), Aragua (7 samples), Barinas (35 samples), Cojedes (8 samples), Monagas (19 samples), and Portuguesa (17 samples). In these states, the average daytime temperature was 26°C, but the average was higher (>28°C) during the dry season. Samples were collected during the rainy season because high temperatures and dry field conditions appeared to suppress symptom expression, while cooler conditions tended to favor symptom development (2). Roots of sampled cassava plants were examined for the presence of FSD. A single 70- to 80-cm-long stem cutting was taken from each plant and subdivided into four pieces. Two pieces were used as rootstocks in graft-inoculation tests with Secundina scions for FSD detection, and two pieces were potted in sterilized soil to be used in other tests. All potted and grafted plants were kept in the Vegetable Virology Laboratory of the Faculty of Agronomy (Universidad Central de Venezuela), at an average temperature of 24°C and 80% relative humidity. FSD-infected plants were identified by mosaic symptoms on Secundina scions and the presence of 80-nm spherical viral particles. Most FSD-infected cultivars expressed only root symptoms. However, in the case of Secundina cvs. MCOL 22 and MCOL 113, foliar symptoms were also detected (1). FSD was found in a simple infection in one cassava sample from Aragua State (14.3% incidence, 1 of 7 samples) and in four cassava samples from Barinas State (11.4% incidence, 4 of 35 samples) associated with Cassava virus X (detected by double-antibody sandwich enzyme-linked immunosorbent assay). To our knowledge, this is the first report of FSD detection in Venezuela. References: (1) E. A. Frison et al. Informe Anual. CIAT, Cali, Colombia, 1995. (2) B. L. Nolt et al. Plant Pathol. 41:384, 1992. (3) Technical Guidelines for the Safe Movement of Cassava Rome. FAO/IBPGR. p. 10-27, 1991.


2-mercaptoethanol restores the ability of nuclear factor kappa B (NF kappa B) to bind DNA in nuclear extracts from interleukin 1-treated cells incubated with pyrollidine dithiocarbamate (PDTC). Evidence for oxidation of glutathione in the mechanism of inhibition of NF kappa B by PDTC.
The metal chelator and anti-oxidant pyrollidine dithiocarbamate (PDTC) has been used extensively in studies implicating reactive oxygen intermediates in the activation of nuclear factor kappa B (NF kappa B). In agreement with other studies, we have shown that PDTC inhibits NF kappa B activation in response to the pro-inflammatory cytokines interleukin 1 (IL1) and tumour necrosis factor (TNF). However, we have found that the inhibition was reversed by treatment of inhibited nuclear extracts with the reducing agent 2-mercaptoethanol. This was observed in extracts prepared from IL1-treated EL4.NOB-1 thymoma cells and TNF-treated Jurkat E6.1 lymphoma cells. These results suggested that the inhibition was caused by oxidation of NF kappa B on a sensitive thiol, possibly on the p50 subunit (which was detected in NF kappa B complexes in both cell types), and not by inhibition of the activation pathway. The possibility that PDTC was acting as a pro-oxidant was therefore investigated. PDTC caused an increase in oxidized glutathione, suggesting that it acts as an oxidizing agent in the cells tested rather than as an anti-oxidant. Similar results were obtained with diamide, a compound designed to oxidize glutathione. Finally, an increase in the ratio of oxidized to reduced glutathione was shown to inhibit NF kappa B-DNA binding in vitro. On the basis of these results we suggest that, while NF kappa B activation is unaffected by PDTC, DNA binding is inhibited through a mechanism involving a shift towards oxidizing conditions, and that this is the mechanism of action of both PDTC and diamide in the cells tested here.


Flight-induced changes in gene expression in the Glanville fritillary butterfly.
Insect flight is one of the most energetically demanding activities in the animal kingdom, yet for many insects flight is necessary for reproduction and foraging. Moreover, dispersal by flight is essential for the viability of species living in fragmented landscapes. Here, working on the Glanville fritillary butterfly (Melitaea cinxia), we use transcriptome sequencing to investigate gene expression changes caused by 15 min of flight in two contrasting populations and the two sexes. Male butterflies and individuals from a large metapopulation had significantly higher peak flight metabolic rate (FMR) than female butterflies and those from a small inbred population. In the pooled data, FMR was significantly positively correlated with genome-wide heterozygosity, a surrogate of individual inbreeding. The flight experiment changed the expression level of 1513 genes, including genes related to major energy metabolism pathways, ribosome biogenesis and RNA processing, and stress and immune responses. Males and butterflies from the population with high FMR had higher basal expression of genes related to energy metabolism, whereas females and butterflies from the small population with low FMR had higher expression of genes related to ribosome/RNA processing and immune response. Following the flight treatment, genes related to energy metabolism were generally down-regulated, while genes related to ribosome/RNA processing and immune response were up-regulated. These results suggest that common molecular mechanisms respond to flight and can influence differences in flight metabolic capacity between populations and sexes.


Murine apolipoprotein serum amyloid A in solution forms a hexamer containing a central channel.
Serum amyloid A (SAA) is a small apolipoprotein that binds to high-density lipoproteins in the serum. Although SAA seems to play a role in host defense and lipid transport and metabolism, its specific functions have not been defined. Despite the growing implications that SAA plays a role in the pathology of various diseases, a high-resolution structure of SAA is lacking because of limited solubility in the high-density lipoprotein-free form. In this study, complementary methods including glutaraldehyde cross-linking, size-exclusion chromatography, and sedimentation-velocity analytical ultracentrifugation were used to show that murine SAA2.2 in aqueous solution exists in a monomer-hexamer equilibrium. Electron microscopy of hexameric SAA2.2 revealed that the subunits are arranged in a ring forming a putative central channel. Limited trypsin proteolysis and mass spectrometry analysis identified a significantly protease-resistant SAA2.2 region comprising residues 39-86. The isolated 39-86 SAA2.2 fragment did not hexamerize, suggesting that part of the N terminus is involved in SAA2.2 hexamer formation. Circular-dichroism spectrum deconvolution and secondary-structure prediction suggest that SAA2.2 contains approximately 50% of its residues in alpha-helical conformation and <10% in beta-structure. These findings are consistent with the recent discovery that human SAA1.1 forms a membrane channel and have important implications for understanding the 3D structure, multiple functions, and pathological roles of this highly conserved protein.


Retroviral-mediated gene transfer in human bone marrow cells growth in continuous perfusion culture vessels.
Hematopoietic stem cell gene therapy holds the promise of being able to treat a variety of inherited and acquired diseases of the hematopoietic stem cell. However, to date, genetic modification of the human hematopoietic stem cell has been relatively inefficient. Here, we report the results of using a bioreactor system to expand hematopoietic cells after a brief retrovirus infection using a high titer, replication defective virus encoding for murine CD18. The retrovirus transduced culture continued to produce genetically modified hematopoietic progenitors for up to 6 weeks, the duration of the culture period. Up to one-third of the long-term culture initiating cell (LTC-IC) are genetically modified by the culture conditions. Murine CD18 can be expressed on the cell surface of up to 20% of the mature cells generated by the culture system, suggesting that clinically significant levels of gene transfer may be occurring. These results demonstrate the feasibility of using continuous perfusion bioreactors as a method of efficiently modifying human hematopoietic stem cells.


Agonist-specific regulation of mu-opioid receptor desensitization and recovery from desensitization.
Agonist-selective actions of opioids on the desensitization of mu-opioid receptors (MORs) have been well characterized, but few if any studies have examined agonist-dependent recovery from desensitization. The outward potassium current induced by several opioids was studied using whole-cell voltage-clamp recordings in locus ceruleus neurons. A brief application of the irreversible opioid antagonist beta-chlornaltrexamine (beta-CNA) was applied immediately after treatment of slices with saturating concentrations of opioid agonists. This approach permitted the measurement of desensitization and recovery from desensitization using multiple opioid agonists, including [Met](5)enkephalin (ME), [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), etorphine, fentanyl, methadone, morphine, morphine-6-glucuronide, oxycodone, and oxymorphone. The results indicate that desensitization protects receptors from irreversible antagonism with beta-CNA. The amount of desensitization was measured as the decrease in current during a 10-min application of a saturating agonist concentration and was a good predictor of the extent of receptor protection from irreversible inactivation with beta-CNA. After desensitization with ME or DAMGO and treatment with beta-CNA, there was an initial profound inhibition of MOR-induced current that recovered significantly after 45 min. There was, however, no recovery of MOR-mediated current with time after treatment with agonists that did not cause desensitization, such as oxycodone. These results demonstrate that desensitization prevents irreversible inactivation of receptors by beta-CNA.


In vitro fermentation gas kinetics and end-products of soluble and insoluble cereal flour dietary fibres are similar.
Insoluble dietary fibre is often considered to be fermented slower and to a lesser extent in (models for) the colon than soluble dietary fibre. However these comparisons are typically made for fibre components of different composition. In the case of fibre from refined cereal flours, there is little difference in fibre composition between soluble and insoluble forms, so effects of solubility on fermentation can be tested without this confounding factor. For each of wheat, rye, and hull-less barley, soluble and insoluble fibre fractions from refined flour and models for baking and extrusion had comparable in vitro fermentation rates and extents, with similar levels of short chain fatty acid metabolites. This study suggests that there should be little difference in the large intestinal nutritional functionality of the soluble and insoluble fibre fractions from cereal grain flours, either unprocessed or after baking or extrusion processing.


Region grouping in natural foliage scenes: image statistics and human performance.
This study investigated the mechanisms of grouping and segregation in natural scenes of close-up foliage, an important class of scenes for human and non-human primates. Close-up foliage images were collected with a digital camera calibrated to match the responses of human L, M, and S cones at each pixel. The images were used to construct a database of hand-segmented leaves and branches that correctly localizes the image region subtended by each object. We considered a task where a visual system is presented with two image patches and is asked to assign a category label (either same or different) depending on whether the patches appear to lie on the same surface or different surfaces. We estimated several approximately ideal classifiers for the task, each of which used a unique set of image properties. Of the image properties considered, we found that ideal classifiers rely primarily on the difference in average intensity and color between patches, and secondarily on the differences in the contrasts between patches. In psychophysical experiments, human performance mirrored the trends predicted by the ideal classifiers. In an initial phase without corrective feedback, human accuracy was slightly below ideal. After practice with feedback, human accuracy was approximately ideal.


Quantum-rotor-induced polarization.
Quantum-rotor-induced polarization is closely related to para-hydrogen-induced polarization. In both cases, the hyperpolarized spin order derives from rotational interaction and the Pauli principle by which the symmetry of the rotational ground state dictates the symmetry of the associated nuclear spin state. In quantum-rotor-induced polarization, there may be several spin states associated with the rotational ground state, and the hyperpolarization is typically generated by hetero-nuclear cross-relaxation. This review discusses preconditions for quantum-rotor-induced polarization for both the 1-dimensional methyl rotor and the asymmetric rotor H217 O@C60 , that is, a single water molecule encapsulated in fullerene C60 . Experimental results are presented for both rotors.


A novel central motor conduction abnormality in D90A-homozygous patients with amyotrophic lateral sclerosis.
Patients with amyotrophic lateral sclerosis (ALS) who are homozygous for the D90A SOD1 mutation have been noted to have central motor abnormalities distinct from those of patients with idiopathic ALS. We stimulated the motor cortex of ten patients homozygous for the D90A SOD1 mutation, using transcranial magnetic stimulation (TMS), and recorded the response evoked in the right first dorsal interosseous muscle when the muscle was at rest and when voluntarily active. A subgroup of patients had two distinct evoked responses when the cortex was stimulated at high intensity with the muscle at rest. When the muscle was modestly contracted, the first of these responses disappeared, whereas the second response was facilitated. Both fast and slow components of the corticospinal tract were usually intact and excited by TMS in these patients. We propose that there is an abnormality of intracortical or intraspinal inhibition in a subgroup of D90A SOD1 ALS patients, which suppresses fast-conducted activity when the muscle is active. Apart from further defining the phenotype of familial ALS, these findings may have importance in understanding the pathogenesis of central motor abnormalities in these patients.


Babesia, Theileria, and Hepatozoon species in ticks infesting animal hosts in Romania.
Babesia spp., Theileria spp., and Hepatozoon spp. are tick-transmitted apicomplexan parasites that cause several important diseases in animals. To increase current knowledge about the diversity of tick-transmitted pathogens in Romania, we investigated the occurrence of Babesia spp., Theileria spp., and Hepatozoon spp. in a wide range of tick species infesting animal hosts. We collected 852 ticks from 10 different animal species from 20 counties in Romania. The assessment was based on detection of parasite DNA by PCR. Five different apicomplexan parasite species were detected; among them three different species of Babesia: B. canis, B. microti, and B. ovis. Hepatozoon canis was the most frequently detected parasite, found predominately in Ixodes ricinus ticks collected from domestic dogs. It was also detected in I. ricinus collected from goat, fox, and cat. Furthermore, H. canis was found in Haemaphysalis punctata and Haemaphysalis concinna ticks. In addition, Theileria buffeli was detected in Rhipicephalus bursa ticks collected from cattle.


Timing functions of the cerebellum.
This study investigated the effects of different types of neurological deficits on timing functions. The performance of Parkinson, cerebellar, cortical, and peripheral neuropathy patients was compared to age-matched control subjects on two separate measures of timing functions. The first task involved the production of timed intervals in which the subjects attempted to maintain a simple rhythm. The second task measured the subjects' perceptual ability to discriminate between small differences in the duration of two intervals. The primacy of the cerebellum in timing functions was demonstrated by the finding that these were the only patients who showed a deficit in both the production and perception of timing tasks. The cerebellar group was found to have increased variability in performing rhythmic tapping and they were less accurate than the other groups in making perceptual discriminations regarding small differences in duration. Critically, this perceptual deficit appears to be specific to the perception of time since the cerebellar patients were unaffected in a control task measuring the perception of loudness. It is argued that the operation of a timing mechanism can be conceptualized as an isolable component of the motor control system. Furthermore, the results suggest that the domain of the cerebellar timing process is not limited to the motor system, but is employed by other perceptual and cognitive systems when temporally predictive computations are needed.


Complete genome sequence of Methanobacterium thermoautotrophicum deltaH: functional analysis and comparative genomics.
The complete 1,751,377-bp sequence of the genome of the thermophilic archaeon Methanobacterium thermoautotrophicum deltaH has been determined by a whole-genome shotgun sequencing approach. A total of 1,855 open reading frames (ORFs) have been identified that appear to encode polypeptides, 844 (46%) of which have been assigned putative functions based on their similarities to database sequences with assigned functions. A total of 514 (28%) of the ORF-encoded polypeptides are related to sequences with unknown functions, and 496 (27%) have little or no homology to sequences in public databases. Comparisons with Eucarya-, Bacteria-, and Archaea-specific databases reveal that 1,013 of the putative gene products (54%) are most similar to polypeptide sequences described previously for other organisms in the domain Archaea. Comparisons with the Methanococcus jannaschii genome data underline the extensive divergence that has occurred between these two methanogens; only 352 (19%) of M. thermoautotrophicum ORFs encode sequences that are >50% identical to M. jannaschii polypeptides, and there is little conservation in the relative locations of orthologous genes. When the M. thermoautotrophicum ORFs are compared to sequences from only the eucaryal and bacterial domains, 786 (42%) are more similar to bacterial sequences and 241 (13%) are more similar to eucaryal sequences. The bacterial domain-like gene products include the majority of those predicted to be involved in cofactor and small molecule biosyntheses, intermediary metabolism, transport, nitrogen fixation, regulatory functions, and interactions with the environment. Most proteins predicted to be involved in DNA metabolism, transcription, and translation are more similar to eucaryal sequences. Gene structure and organization have features that are typical of the Bacteria, including genes that encode polypeptides closely related to eucaryal proteins. There are 24 polypeptides that could form two-component sensor kinase-response regulator systems and homologs of the bacterial Hsp70-response proteins DnaK and DnaJ, which are notably absent in M. jannaschii. DNA replication initiation and chromosome packaging in M. thermoautotrophicum are predicted to have eucaryal features, based on the presence of two Cdc6 homologs and three histones; however, the presence of an ftsZ gene indicates a bacterial type of cell division initiation. The DNA polymerases include an X-family repair type and an unusual archaeal B type formed by two separate polypeptides. The DNA-dependent RNA polymerase (RNAP) subunits A', A", B', B" and H are encoded in a typical archaeal RNAP operon, although a second A' subunit-encoding gene is present at a remote location. There are two rRNA operons, and 39 tRNA genes are dispersed around the genome, although most of these occur in clusters. Three of the tRNA genes have introns, including the tRNAPro (GGG) gene, which contains a second intron at an unprecedented location. There is no selenocysteinyl-tRNA gene nor evidence for classically organized IS elements, prophages, or plasmids. The genome contains one intein and two extended repeats (3.6 and 8.6 kb) that are members of a family with 18 representatives in the M. jannaschii genome.


A simulation tool for dynamic contrast enhanced MRI.
The quantification of bolus-tracking MRI techniques remains challenging. The acquisition usually relies on one contrast and the analysis on a simplified model of the various phenomena that arise within a voxel, leading to inaccurate perfusion estimates. To evaluate how simplifications in the interstitial model impact perfusion estimates, we propose a numerical tool to simulate the MR signal provided by a dynamic contrast enhanced (DCE) MRI experiment. Our model encompasses the intrinsic R1 and R2 relaxations, the magnetic field perturbations induced by susceptibility interfaces (vessels and cells), the diffusion of the water protons, the blood flow, the permeability of the vessel wall to the the contrast agent (CA) and the constrained diffusion of the CA within the voxel. The blood compartment is modeled as a uniform compartment. The different blocks of the simulation are validated and compared to classical models. The impact of the CA diffusivity on the permeability and blood volume estimates is evaluated. Simulations demonstrate that the CA diffusivity slightly impacts the permeability estimates (< 5% for classical blood flow and CA diffusion). The effect of long echo times is investigated. Simulations show that DCE-MRI performed with an echo time TE = 5 ms may already lead to significant underestimation of the blood volume (up to 30% lower for brain tumor permeability values). The potential and the versatility of the proposed implementation are evaluated by running the simulation with realistic vascular geometry obtained from two photons microscopy and with impermeable cells in the extravascular environment. In conclusion, the proposed simulation tool describes DCE-MRI experiments and may be used to evaluate and optimize acquisition and processing strategies.


Risk of gastrointestinal illness associated with the consumption of rainwater: a systematic review.
The collection of rainwater for human consumption is a practice well established in many parts of the world. Much of the research to date regarding this inexpensive and sustainable source has focused on its microbiological or chemical quality and there have been no reviews of epidemiological evidence regarding actual health risks associated with rainwater consumption. Electronic bibliographic databases were searched for epidemiological studies that attempted to quantify the risk of gastrointestinal disease linked to the consumption of harvested rainwater. Online databases were searched from the oldest date up to January 2011. Both observational and experimental studies were included. In addition, reference sections of key articles were searched and authors of previous studies were contacted where appropriate. Studies were assessed for relevance independently and in duplicate. Searches returned a total of 764 articles, 13 met inclusion criteria, 5 of these were outbreak reports, and 9 were studies of other design types. Pooled subgroup analysis suggests that rainwater is associated with reduced risk of illness compared to unimproved supplies (relative risk 0.57 95% CI 0.42, 0.77). There was no significant difference in risk in the pooled analysis of studies that compared rainwater to improved water supplies (relative risk 0.82 95% CI 0.38, 1.73). However, there was heterogeneity with one study showing an excess risk of campylobacteriosis. Classification of outbreak reports determined that 4 reports were "strongly associated with rainwater" while 1 report was "probably associated with rainwater". We conclude that the evidence suggests that rainwater is safer than water from unimproved water supplies. Where feasible rainwater harvesting should be encouraged as a step toward achieving millennium development targets.


Impact-shocked rocks--insights into Archean and extraterrestrial microbial habitats (and sites for prebiotic chemistry?).
Impact-shocked gneiss shocked to greater than 10 GPa in the Haughton impact structure in the Canadian High Arctic has an approximately 25-times greater pore surface area than unshocked rocks. These pore spaces provide microhabitats for a diversity of heterotrophic microorganisms and in the near-surface environment of the rocks, where light levels are sufficient, cyanobacteria. Shocked rocks provide a moisture retaining, UV protected microenvironment. During the Archean, when impact fluxes were more than two orders of magnitude higher than today, the shocked-rock habitat was one of the most common terrestrial habitats and might have provided a UV-shielded refugium for primitive life. These potential habitats are in high abundance on Mars where impact crater habitats could have existed over geologic time periods of billions of years, suggesting that impact-shocked rocks are important sites to search for biomolecules in extraterrestrial life detection strategies. In addition to being favourable sites for life, during the prebiotic period of planetary history impact-shocked rocks might have acted as a site for the concentration of reactants for prebiotic syntheses.


A nonsurgical approach to low back pain.
Low back pain, a leading cause of disability in the United States, has a significant economic impact not only on lost productivity but also on healthcare expenditures. Approximately a fifth of patients will see multiple physicians in their quest for relief of low back pain. Primary care physicians therefore play a crucial role in the initial approach to these patients. A thorough history and physical examination directed toward the neurologic, orthopedic, and osteopathic evaluation are essential. This article reviews the diagnosis and assessment of pain levels and a triad system of therapy involving cortical, spinal, and peripheral levels. Options include antidepressants, neuroleptics, neurostimulants, and osteopathic manipulative treatment (OMT) (cortical level); opiates, tramadol hydrochloride, and transcutaneous electrical nerve stimulators (spinal level); and nonsteroidal anti-inflammatory drugs, epidural injections, spinal blocks, antispasmodics, physical therapy, muscle relaxants, exercise, and OMT (peripheral level), By choosing a modality directed at each level, the clinician may provide the patient with a pain management program that will maximize the chosen mode of therapy and restore function and mobility.


Swedish Nurse Anesthetists' Experiences of the WHO Surgical Safety Checklist.
The World Health Organization (WHO) surgical safety checklist aims to increase communication, build teamwork, and standardize routines in clinical practice in an effort to reduce complications and improve patient safety. The checklist has been implemented in surgical departments both nationally and internationally. The purpose of this study was to describe the registered nurse anesthetists' (RNA) experience with the use of the WHO surgical safety checklist. This was a cross-sectional study with a descriptive mixed methods design, involving nurse anesthetists from two different hospitals in Sweden. Data were collected using a study-specific questionnaire. Forty-seven RNAs answered the questionnaire. There was a statistically significant lower compliance to "Sign-in" compared with the other two parts, "Timeout" and "Sign-out." The RNAs expressed that the checklist was very important for anesthetic and perioperative care. They also expressed that by confirming their own area of expertise, they achieved an increased sense of being a team member. Thirty-four percent believed that the surgeon was responsible for the checklist, yet this was not the reality in clinical practice. Although 23% reported that they initiated use of the checklist, only one RNA believed that it was the responsibility of the RNA. Forty-three percent had received training about the checklist and its use. The WHO surgical checklist facilitates the nurse anesthetist's anesthetic and perioperative care. It allows the nurse anesthetist to better identify each patient's specific concerns and have an increased sense of being a team member.


Cytoplasmic recycling of 60S preribosomal factors depends on the AAA protein Drg1.
Allelic forms of DRG1/AFG2 confer resistance to the drug diazaborine, an inhibitor of ribosome biogenesis in Saccharomyces cerevisiae. Our results show that the AAA-ATPase Drg1 is essential for 60S maturation and associates with 60S precursor particles in the cytoplasm. Functional inactivation of Drg1 leads to an increased cytoplasmic localization of shuttling pre-60S maturation factors like Rlp24, Arx1, and Tif6. Surprisingly, Nog1, a nuclear pre-60S factor, was also relocalized to the cytoplasm under these conditions, suggesting that it is a previously unsuspected shuttling preribosomal factor that is exported with the precursor particles and very rapidly reimported. Proteins that became cytoplasmic under drg1 mutant conditions were blocked on pre-60S particles at a step that precedes the association of Rei1, a later-acting preribosomal factor. A similar cytoplasmic accumulation of Nog1 and Rlp24 in pre-60S-bound form could be seen after overexpression of a dominant-negative Drg1 variant mutated in the D2 ATPase domain. We conclude that the ATPase activity of Drg1 is required for the release of shuttling proteins from the pre-60S particles shortly after their nuclear export. This early cytoplasmic release reaction defines a novel step in eukaryotic ribosome maturation.


Intestinal parasitic infections in human immunodeficiency virus (HIV)-positive and HIV-negative individuals in San Pedro Sula, Honduras.
Honduras has at least five-times more human immunodeficiency virus (HIV)-infected individuals than any other country in Central America. The relationship between HIV status and the presence of intestinal parasites in this part of the world is unknown. This study presents the results from a prospective, comparative study for the presence of parasites in 52 HIV-positive and 48 HIV-negative persons in San Pedro Sula, Honduras. Infection with HIV was determined by microagglutination and confirmed by Western blot analysis. Parasites were detected in stools using formalin-ether concentration, and Kinyoun and trichrome staining. Age, sex, and clinical state of HIV infection were recorded for each study participant. Our results indicate that Cryptosporidium parvum and Strongyloides stercoralis, which are intracellular or live in the mucosa, were found exclusively in persons infected with HIV. In comparison, the prevalence of the extracellular parasites Giardia lamblia, Ascaris lumbricoides, and Trichuris trichiura was significantly higher (P < 0.05) in persons who were HIV-negative. Trichuris worms are in contact with the gut epithelium and less so with the mucosa, whereas Strongyloides lives within the gut mucosa. It is possible that changes in the gut epithelium due to HIV infection do not affect the mucosa and therefore would not affect Strongyloides. We conclude that infection with HIV may selectively deter the establishment of certain intestinal parasites. This may be due to the fact that HIV-induced enteropathy does not favor the establishment of extracellular parasites. Intracellular and mucosal dwelling organisms, however, may benefit from pathologic changes and reduced local immune responses induced by the virus, which, in turn, may lead to higher prevalence among HIV-infected individuals.


Celecoxib compared with sustained-release paracetamol for osteoarthritis: a series of n-of-1 trials.
To assess the use of n-of-1 trials for short-term choice of drugs for osteoarthritis, with particular reference to comparing the efficacy of sustained-release [SR] paracetamol with celecoxib in individual patients. Evaluation of community-based patients undergoing n-of-1 trials which consisted of double-blind, crossover comparisons of celecoxib 200 or 400 mg/day with sustained-release paracetamol 1330 mg three times a day in three pairs of 2 week treatment periods per drug with random order of the drugs within pairs. Outcomes evaluated were pain and stiffness in sites nominated by the patient, functional limitation scores, preferred medication, side effects and changes in drug use after an n-of-1 trial. Participants were 59 patients with osteoarthritis in multiple sites (hip 6, knee 24, hand 6, shoulder/neck 8, back 14, foot 5), with pain for >or=1 month severe enough to warrant consideration of long-term use of celecoxib but for whom there was doubt about its efficacy. Forty-one n-of-1 trials were completed. Although on average, celecoxib showed better scores than SR paracetamol [0.2 (0.1) for pain, 0.3 (0.1) for stiffness and 0.3 (0.1) for functional limitation], 33 of the 41 individual patients (80%) failed to identify the differences between SR paracetamol and celecoxib in terms of overall symptom relief. Of the eight patients who were able to identify the differences, seven had better relief with celecoxib and one with SR paracetamol. In 25 out of 41 [61%] patients, subsequent management was consistent with their trial results. N-of-1 trials may provide a rational and effective method to best choose drugs for individuals with osteoarthritis. SR paracetamol is more useful than celecoxib for most patients of whom management is uncertain.


Structured-light-based highly dense and robust 3D reconstruction.
In this paper, a structured-light-based highly dense and robust 3D reconstruction method is proposed by combining a Gray code and region-shifting pattern. The region-shifting pattern is transformed to the trapezoidal and triangle wave shifting pattern by combining all frames of the region-shifting pattern, and then the boundary of the trapezoidal wave shifting pattern and the peak and phase of the triangle wave shifting pattern are estimated. Through this technique, the spatial resolution is increased about three times. Consequently, the 3D points are reconstructed with a resolution much higher than a camera image resolution. Moreover, as the proposed method measures the boundary and the peak with all frames, it increases the signal-to-noise ratio and is more robust than the conventional methods that use only one or two frames to detect them.


Smothering in UK free-range flocks. Part 1: incidence, location, timing and management.
Smothering in poultry is an economic and welfare-related concern. This study presents the first results from a questionnaire addressing the incidence, location, timing and management of smothering of free-range farm managers from two commercial egg companies (representing 35 per cent of the UK free-range egg supply). Overall, nearly 60 per cent of farm mangers experienced smothering in their last flock, with an average of 25.5 birds lost per incidence, although per cent mortality due to smothering was low (x̄=1.6 per cent). The majority of farm managers also reported that over 50 per cent of all their flocks placed had been affected by smothering. The location and timing of smothering (excluding smothering in nest boxes) tended to be unpredictable and varied between farms. Blocking off corners/nest boxes and walking birds more frequently were identified as popular smothering reduction measures, although there was a wide variety of reduction measures reported overall. The motivation to implement reduction measures was related to a farm manager's previous experience of smothering. To our knowledge, this is the first study to provide a representative industry estimate on the incidence, location, timing and management of smothering. The results suggest that smothering is a common problem, unpredictable between flocks with no clear, effective reduction strategies. A follow-up study will investigate the correlations among smothering, disease and other welfare problems and may shed further light on management solutions.


Multiscale methods framework: self-consistent coupling of molecular theory of solvation with quantum chemistry, molecular simulations, and dissipative particle dynamics.
In this work, we will address different aspects of self-consistent field coupling of computational chemistry methods at different time and length scales in modern materials and biomolecular science. Multiscale methods framework yields dramatically improved accuracy, efficiency, and applicability by coupling models and methods on different scales. This field benefits many areas of research and applications by providing fundamental understanding and predictions. It could also play a particular role in commercialization by guiding new developments and by allowing quick evaluation of prospective research projects. We employ molecular theory of solvation which allows us to accurately introduce the effect of the environment on complex nano-, macro-, and biomolecular systems. The uniqueness of this method is that it can be naturally coupled with the whole range of computational chemistry approaches, including QM, MM, and coarse graining.


Nonlinearities make a difference: comparison of two common Hill-type models with real muscle.
Compared to complex structural Huxley-type models, Hill-type models phenomenologically describe muscle contraction using only few state variables. The Hill-type models dominate in the ever expanding field of musculoskeletal simulations for simplicity and low computational cost. Reasonable parameters are required to gain insight into mechanics of movement. The two most common Hill-type muscle models used contain three components. The series elastic component is connected in series to the contractile component. A parallel elastic component is either connected in parallel to both the contractile and the series elastic component (model [CC+SEC]), or is connected in parallel only with the contractile component (model [CC]). As soon as at least one of the components exhibits substantial nonlinearities, as, e.g., the contractile component by the ability to turn on and off, the two models are mechanically different. We tested which model ([CC+SEC] or [CC]) represents the cat soleus better. Ramp experiments consisting of an isometric and an isokinetic part were performed with an in situ cat soleus preparation using supramaximal nerve stimulation. Hill-type models containing force-length and force-velocity relationship, excitation-contraction coupling and series and parallel elastic force-elongation relations were fitted to the data. To test which model might represent the muscle better, the obtained parameters were compared with experimentally determined parameters. Determined in situations with negligible passive force, the force-velocity relation and the series elastic component relation are independent of the chosen model. In contrast to model [CC+SEC], these relations predicted by model [CC] were in accordance with experimental relations. In conclusion model [CC] seemed to better represent the cat soleus contraction dynamics and should be preferred in the nonlinear regression of muscle parameters and in musculoskeletal modeling.


The evolution of lying in well-mixed populations.
Lies can have profoundly negative consequences for individuals, groups and even for societies. Understanding how lying evolves and when it proliferates is therefore of significant importance for our personal and societal well-being. To that effect, we here study the sender-receiver game in well-mixed populations with methods of statistical physics. We use the Monte Carlo method to determine the stationary frequencies of liars and believers for four different lie types. We consider altruistic white lies that favour the receiver at a cost to the sender, black lies that favour the sender at a cost to the receiver, spiteful lies that harm both the sender and the receiver, and Pareto white lies that favour both the sender and the receiver. We find that spiteful lies give rise to trivial behaviour, where senders quickly learn that their best strategy is to send a truthful message, while receivers likewise quickly learn that their best strategy is to believe the sender's message. For altruistic white lies and black lies, we find that most senders lie while most receivers do not believe the sender's message, but the exact frequencies of liars and non-believers depend significantly on the payoffs, and they also evolve non-monotonically before reaching the stationary state. Lastly, for Pareto white lies we observe the most complex dynamics, with the possibility of both lying and believing evolving with all frequencies between 0 and 1 in dependence on the payoffs. We discuss the implications of these results for moral behaviour in human experiments.


Cardiovascular risk scores: qualitative study of how primary care practitioners understand and use them.
The National Institute for Health and Care Excellence guidelines and the Quality Outcomes Framework require practitioners to use cardiovascular risk scores in assessments for the primary prevention of cardiovascular disease. To explore GPs understanding and use of cardiovascular risk scores. Qualitative study with purposive maximum variation sampling of 20 GPs working in Oxfordshire, UK. Method Thematic analysis of transcriptions of face-to-face interviews with participants undertaken by two individuals (one clinical, one non-clinical). GPs use cardiovascular risk scores primarily to guide treatment decisions by estimating the risk of a vascular event if the patient remains untreated. They expressed considerable uncertainty about how and whether to take account of existing drug treatment or other types of prior risk modification. They were also unclear about the choice between the older scores, based on the Framingham study, and newer scores, such as QRISK. There was substantial variation in opinion about whether scores could legitimately be used to illustrate to patients the change in risk as a result of treatment. The overall impression was of considerable confusion. The drive to estimate risk more precisely by qualifying guidance and promoting new scores based on partially-treated populations appears to have created unnecessary confusion for little obvious benefit. National guidance needs to be simplified, and, to be fit for purpose, better reflect the ways in which cardiovascular risk scores are currently used in general practice. Patients may be better served by simple advice to use a Framingham score and exercise more clinical judgement, explaining to patients the necessary imprecision of any individual estimate of risk.


Supportive housing for the chronically mentally ill. Matching clients with community environments.
The need for permanent housing for the chronically mentally ill has received a great deal of attention over the last several years. One response to the problem has been the development of supportive housing, that is, non-facility-based permanent homes with placement based on clients' functional capabilities and preferences. However, little research has focused on assessing the match between clients and environmental requirements. This study begins to identify the social and clinical characteristics of clients that contribute to selection into different types of housing environments. Ninety-one clients were sampled from the supportive housing services of a major provider in two New England states. Logistic regression was used to estimate the probability that clients will be placed into apartments vs. other, more restricted settings, based on their clinical and social characteristics. Findings show that the primary determinants of placement were clinical severity, early family history, and adequacy of family support. The less severely ill and better functioning the client, the more likely that he or she was placed in an apartment. This was mitigated, however, by the availability and adequacy of family support. In addition, clients with early family disruptions were also less likely to be placed in apartments. Findings are discussed in light of their implications for providing permanent housing placements for chronically mentally ill persons and for factors in future research to evaluate the success of placement.


Early Detection and Treatment of Type 2 Diabetes Reduce Cardiovascular Morbidity and Mortality: A Simulation of the Results of the Anglo-Danish-Dutch Study of Intensive Treatment in People With Screen-Detected Diabetes in Primary Care (ADDITION-Europe).
To estimate the benefits of screening and early treatment of type 2 diabetes compared with no screening and late treatment using a simulation model with data from the ADDITION-Europe study. We used the Michigan Model, a validated computer simulation model, and data from the ADDITION-Europe study to estimate the absolute risk of cardiovascular outcomes and the relative risk reduction associated with screening and intensive treatment, screening and routine treatment, and no screening with a 3- or 6-year delay in the diagnosis and routine treatment of diabetes and cardiovascular risk factors. When the computer simulation model was programmed with the baseline demographic and clinical characteristics of the ADDITION-Europe population, it accurately predicted the empiric results of the trial. The simulated absolute risk reduction and relative risk reduction were substantially greater at 5 years with screening, early diagnosis, and routine treatment compared with scenarios in which there was a 3-year (3.3% absolute risk reduction [ARR], 29% relative risk reduction [RRR]) or a 6-year (4.9% ARR, 38% RRR) delay in diagnosis and routine treatment of diabetes and cardiovascular risk factors. Major benefits are likely to accrue from the early diagnosis and treatment of glycemia and cardiovascular risk factors in type 2 diabetes. The intensity of glucose, blood pressure, and cholesterol treatment after diagnosis is less important than the time of its initiation. Screening for type 2 diabetes to reduce the lead time between diabetes onset and clinical diagnosis and to allow for prompt multifactorial treatment is warranted.


Phenoxybenzamine treatment differentiates dopaminergic 3H-ligand binding sites in bovine caudate membranes.
Phenoxybenzamine, the classic alpha-adrenergic receptor alkylating agent, also acts as an irreversible antagonist of the binding of [3H]spiroperidol, a D-2-selective dopaminergic ligand, to bovine caudate membranes. Doses completely eliminating the binding of this ligand leave the binding of [3H]dopamine to D-3 sites virtually unaffected. The binding sites for these two ligands thus represent distinct subtypes of dopamine receptors, not interconverting states of a single receptor. This phenoxybenzamine-mediated inhibition proceeds via a dose-dependent (pseudo-IC50 = 1 microM) decrease in Bmax with little or no change in affinity for 3H-ligands at the D-2 site. The effect is site-directed, as the dopaminergic agonists dopamine and apomorphine and the antagonist domperidone are able to protect against phenoxybenzamine-mediated attack in proportion to their affinities for D-2 sites. Epinephrine, norepinephrine, and serotonin are much less effective in protecting these sites. The sensitivity of [3H]apomorphine binding is intermediate to that of [3H]spiroperidol and [3H]dopamine. [3H]Apomorphine binding can be resolved into a phenoxybenzamine-labile population of binding sites which have equal phenoxybenzamine sensitivity, selectivity among protecting agents, and butyrophenone affinity to those of D-2 sites labeled by 3H-butyrophenones, and a separate phenoxybenzamine-stable population of sites which have an affinity for dopamine comparable to that of D-3 sites labeled by [3H]dopamine. [3H]Apomorphine therefore appears to label a portion of D-2 receptor sites in addition to D-3 receptors.


A combined randomised and observational study of surgery for fractures in the distal radius in the elderly (CROSSFIRE)-a study protocol.
Fractures of the distal radius are common and occur in all age groups. The incidence is high in older populations due to osteoporosis and increased falls risk. Considerable practice variation exists in the management of distal radius fractures in older patients ranging from closed reduction with cast immobilisation to open reduction with plate fixation. Plating is currently the most common surgical treatment. While there is evidence showing no significant advantage for some forms of surgical fixation over conservative treatment, and no difference between different surgical techniques, there is a lack of evidence comparing two of the most common treatments used: closed reduction and casting versus plating. Surgical management involves significant costs and risks compared with conservative management. High-level evidence is required to address practice variation, justify costs and to provide the best clinical outcomes for patients. This pragmatic, multicentre randomised comparative effectiveness trial aims to determine whether plating leads to better pain and function and is more cost-effective than closed reduction and casting of displaced distal radius fractures in adults aged 60 years and older. The trial will compare the two techniques but will also follow consenting patients who are unwilling to be randomised in a separate, observational cohort. Inclusion of non-randomised patients addresses selection bias, provides practice and outcome insights about standard care, and improves the generalisability of the results from the randomised trial. CROSSFIRE(Combined Randomised and Observational Study of Surgery for Fractures In the distal Radius in the Elderly) was reviewed and approved by The Hunter New England HREC (HNEHREC Reference No: 16/02/17/3.04). The results of the trial will be published in a peer-reviewed journal and will be disseminated via various forms of media. Results will be incorporated in clinical recommendations and practice guidelines produced by professional bodies. CROSSFIRE has been registered with the Australian and New Zealand Clinical Trials Registry (ANZCTR: ACTRN12616000969460).


Object-centred spatial reference in 4-month-old infants.
An appreciation of object-centred spatial relations involves representing a 'within-object' spatial relation across changes in the object orientation. This representational ability is important in adult object recognition [Biederman, I. (1987). Recognition-by-components: A theory of human image understanding. Psychological Review, 94, 115-147; Marr, D., & Nishihara, H. K. (1978). Representation and recognition of the spatial organisation of three-dimensional structure. Proceedings of the Royal Society of London, Series B (Biological Sciences), 200, 269-294; Tarr, M. J., & Pinker, S. (1990). When does human object recognition use a viewer-centred reference frame? Psychological Science, 1, 253-256] and is also thought to be a fundamental component of the mature object concept [Piaget, J. (1954). The Construction of Reality in the Child. Routledge & Kegan-Paul: London, UK. (Originally published in French in 1937)]. An experiment is reported in which eighteen 4-month-old infants were familiarised to a specific spatial relation within an object, across six different orientations of the object. On subsequent test trials the object was presented to the infants in an entirely novel orientation. Between successive test trials the within-object spatial relation was alternated between novel and familiar. The infants demonstrated significant sensitivity of their looking to both the novelty of the stimuli and the order in which novel and familiar stimuli were presented. It is concluded that by 4 months of age infants are able to form object-centred spatial frames of reference. These findings are discussed in the light of our current understanding of the development of object representation during infancy.


Postoperative pain control for primary cleft lip repair in infants: is there an advantage in performing peripheral nerve blocks?
Primary cleft lip repair is performed in infants under 1 year of age. The efficacy of an infraorbital nerve block vs intravenous fentanyl was compared in our prospective, randomized controlled trial. Forty-six infants scheduled for primary cleft lip repair were prospectively randomized to one of two groups: group F that received 2 mcg x kg(-1) of fentanyl intravenously and an infraorbital nerve block with 0.5 ml on each side of preservative-free normal saline, and, group B that received bilateral infraorbital nerve blocks with 0.5 ml on each side of 0.25% bupivacaine and 2 ml of preservative-free saline solution intravenously after induction of anesthesia but prior to surgical incision. Patients were observed by a blinded observer for (i) pain scores using neonatal infant pain score; (ii) need for rescue medication in the anesthesia care unit (PACU), in the short stay unit (SSU) and at home and (iii) feeding parameters including difficulty in feeding, time to first feeding and volume of feeds in the PACU, SSU and at home. There were no significant differences in pain scores between the two groups over time (P = 0.98); there were no differences between groups in the number of rescue medications in the PACU, in the SSU as well as at home; however, the time to first rescue medication was greater in the block group compared with the fentanyl group (P = 0.07). There were no significant differences in feeding volumes between groups in the PACU (P = 0.46), SSU (P = 0.57) and at home (P = 0.15). There were no differences in time to initiate feeding between the two groups (P = 0.81). However, there was difficulty with feeding in the block groups compared with the fentanyl group (P = 0.01). The infraorbital nerve block can be effectively used for pain control in infants undergoing primary cleft lip repair. Although children undergoing a nerve block experienced minor difficulties in feeding, there were no differences in feeding volumes or other feeding parameters. This study has shed light into postoperative outcomes besides pain control on children undergoing cleft lip repairs.


Acute Aerobic Exercise-Induced Motor Priming Improves Piano Performance and Alters Motor Cortex Activation.
Acute aerobic exercise has been shown to improve fine motor skills and alter activation of the motor cortex (M1). The intensity of exercise may influence M1 activation, and further impact whole-body motor skill performance. The aims of the current study were to compare a whole-body motor skill via a piano task following moderate-intensity training (MIT) and high-intensity interval training (HIIT), and to determine if M1 activation is linked to any such changes in performance. Nine subjects (seven females and two males), aged 18 ± 1 years completed a control, MIT, and HIIT trial followed by administration of a piano performance task. M1 activation was evaluated by measuring oxyhemoglobin (O2Hb) and hemoglobin difference (Hbdiff) changes during post-exercise piano performance using functional near-infrared spectroscopy (fNIRS). The results indicate that piano performance scores were higher after the MIT trial, but not HIIT trial, compared to the control trial. A negative relationship was detected between heart rate during HIIT and post-HIIT piano scores. M1 activation (as measured by Hbdiff) was significantly increased after the HIIT trial. M1 activation was also positively associated with piano performance when exercise trials (HIIT + MIT) and all trials (HIIT + MIT + Control) were combined. We found that acute moderate-intensity exercise led to an improvement in complex motor skill performance while higher-intensity exercise increased M1 activation. These results demonstrate that moderate-intensity exercise can prime the nervous system for the acquisition of whole-body motor skills, suggesting that similar exercise protocols may be effective in improving the outcomes of other motor tasks performed during regular routines of daily life (e.g., sporting tasks, activities of daily living or rehabilitation). In addition, it appears that improvements in motor task performance may be driven by M1 activation. Our findings provide new mechanistic insight into the complex relationship between exercise intensity, M1 activation, and whole-body motor skill performance.


Comorbidity and personality traits in patients with different levels of posttraumatic stress disorder following myocardial infarction.
More research is needed to further our understanding of posttraumatic stress responses and comorbidity following myocardial infarction (MI), and to help us identify more clearly the personality traits which indicate that a person is more prone to developing post-MI posttraumatic stress disorder (PTSD). This study aimed to 1) investigate the comorbidity of patients who suffered from different levels of posttraumatic stress disorder following myocardial infarction (i.e. post-MI PTSD), and 2) investigate to what extent patients with different levels of post-MI PTSD differed in their personality traits. One hundred and twenty MI patients from two general practices were recruited for the study. They were asked to complete the Posttraumatic Stress Diagnostic Scale (PDS), the General Health Questionnaire-28 (GHQ-28) and the NEO-Five Factor Inventory (NEO-FFI). They were divided into a no-PTSD group, a partial-PTSD group and a full-PTSD group, according to the scores of the PDS. One hundred and sixteen members of the general public were also recruited for comparison purposes. They were asked to complete the GHQ-28. The results showed that patients with full-PTSD reported significantly more somatic problems, anxiety, social dysfunction and depression than the other two patient groups and the control group. When age, bypass surgery, mental health problems before MI and angioplasty were controlled for, patients with full-PTSD also reported greater symptom severity of the four GHQ subscales than the other two patient groups. Patients with full-PTSD were significantly more neurotic than those with no-PTSD and partial-PTSD. Patients with full-PTSD were less agreeable than patients with no-PTSD. Regression analyses showed that personality did not moderate the relationship between PTSD and comorbidity. To conclude, following MI, those with full-PTSD tend to report more severe comorbidity than those who have not developed PTSD fully. The former can also be distinguished from the latter by virtue of their specific personality traits.