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The ShcA adapter protein is necessary for early embryonic development. The role of ShcA in development is primarily attributed to its 52 and 46 kDa isoforms that transduce receptor tyrosine kinase signaling through the extracellular signal regulated kinase (ERK). During embryogenesis, ERK acts as the primary signaling effector, driving fate acquisition and germ layer specification. P66Shc, the largest of the ShcA isoforms, has been observed to antagonize ERK in several contexts; however, its role during embryonic development remains poorly understood. We hypothesized that p66Shc could act as a negative regulator of ERK activity during embryonic development, antagonizing early lineage commitment. To explore the role of p66Shc in stem cell self-renewal and differentiation, we created a p66Shc knockout murine embryonic stem cell (mESC) line. Deletion of p66Shc enhanced basal ERK activity, but surprisingly, instead of inducing mESC differentiation, loss of p66Shc enhanced the expression of core and naive pluripotency markers. Using pharmacologic inhibitors to interrogate potential signaling mechanisms, we discovered that p66Shc deletion permits the self-renewal of naive mESCs in the absence of conventional growth factors, by increasing their responsiveness to leukemia inhibitory factor (LIF). We discovered that loss of p66Shc enhanced not only increased ERK phosphorylation but also increased phosphorylation of Signal transducer and activator of transcription in mESCs, which may be acting to stabilize their naive-like identity, desensitizing them to ERK-mediated differentiation cues. These findings identify p66Shc as a regulator of both LIF-mediated ESC pluripotency and of signaling cascades that initiate postimplantation embryonic development and ESC commitment. [ABSTRACT FROM AUTHOR]

Reactions of molecules on metal surfaces are notoriously difficult to simulate accurately. Density functional theory can be utilized to generate a potential energy surface, but with presently available functionals, the results are not yet accurate enough. To provide benchmark barrier heights with a high-quality method, diffusion Monte Carlo (DMC) is applied to H2 + Al(110). Barrier heights have been computed for six geometries. Our present goal is twofold: first, to provide accurate barrier heights for the two lowest lying transition states of the system, and second, to assess whether density functionals are capable of describing the variation of barrier height with molecular orientation and impact site through a comparison with DMC barriers. To this end, barrier heights computed with selected functionals at the generalized gradient approximation (GGA) and meta-GGA levels are compared to the DMC results. The comparison shows that all selected functionals yield a rather accurate description of the variation of barrier heights with impact site and orientation, although their absolute values may not be accurate. RPBE-vdW-DF and BEEF-vdW were found to perform quite well even in terms of absolute numbers. Both functionals provided barrier heights for the energetically lowest lying transition state that are within 1 kcal/mol of the DMC value. [ABSTRACT FROM AUTHOR]

"Common-sense" physical activity (PA) interventions for older adults may be more effective if developed in accordance with behavior change theory. One way to achieve this is through retrospectively applying a theoretical behavior change framework to "reverse code" an existing intervention and guide its ongoing development. This study aimed to detail a clear and systematic procedure that applied elements of the Behaviour Change Wheel (BCW) framework to reverse code the Active Ageing Pathway (AAP) intervention. The objectives of the procedure were to characterize the content of the AAP and its links to behavior change theory. The content of the AAP was first deconstructed through the examination of "standard operating procedures" documents, in-person observation, and a series of face-to-face discussions with AAP management. Then, the behavior change techniques (BCT) and BCW intervention functions associated with the AAP's content were identified and coded using the BCT Taxonomy version 1. Forty-one active components were identified within the AAP, which involved numerous professionals, and pertained to a diverse and interlinked range of factors, across various modes of delivery. The components were classified under 20 separate BCT labels, which related to eight of the nine BCW intervention functions. These outcomes were demonstrated to have practical applications for identifying gaps in intervention content as well as for guiding future intervention evaluation. This study supports previous work detailing the usefulness of reverse coding procedures as a tool for developing common-sense interventions, and is the first to do so in the context of a PA intervention for older adults. [ABSTRACT FROM AUTHOR]

It is argued that a gap exists between research evidence and "real-world" physical activity (PA) intervention practice. One potential way to aid the translatability of evidence in this field is for researchers to work actively with the public health practitioners and organisations that run PA interventions to engage in co-creative research. This paper reports the process and strategies used to underpin research co-creation during a recent qualitative PA intervention study, and the outcomes of the co-creative approach from the perspective of the public health organisation involved in the research in terms of providing them with translatable evidence. A range of strategies were reported to facilitate co-creation in the study, such as engaging the public health organisation in the identification of the research question and development of the research protocol and involving them in participant recruitment. The cocreative research approach resulted in timely, relevant, and understandable research evidence for the organisation, which was translatable to their real-world PA intervention practice. The evidence provided them with clear actions and information to plan their future work and objectives. This paper demonstrates how a co-creative research approach can potentially help to close the evidence-practice gap in the PA intervention field. [ABSTRACT FROM AUTHOR]

The association/dissociation reaction path for ozone (O2 + O ↔ O3) is notoriously difficult to describe accurately using ab initio electronic structure theory, due to the importance of both strong and dynamic electron correlations. Experimentally, spectroscopic studies of the highest lying recorded vibrational states combined with the observed negative temperature dependence of the kinetics of oxygen isotope exchange reactions confirm that the reaction is barrierless, consistent with the latest potential energy surfaces. Previously reported potentials based on Davidson-corrected internally contracted multireference configuration interaction (MRCI) suffer from a spurious reef feature in the entrance channel even when extrapolated towards the complete basis set limit. Here, we report an analysis of comparisons between a variety of electronic structure methods including internally contracted and uncontracted MRCI (with and without Davidson corrections), as well as full configuration interaction quantum Monte Carlo, fixed-node diffusion Monte Carlo, and density matrix renormalization group. [ABSTRACT FROM AUTHOR]

This paper shows some of the differences and similarities between computation and hypercomputation, the similarities relating to the complexity of propositional computation and the differences being the propositions that can be decided computationally or hypercomputationally. The methods used are ordinal Turing machines with infinitely long programs and diagonalization out of computing complexity classes. The main results are the characterization of inequalities of run time complexities of serial, indeterministic serial and parallel computers and hypercomputers and the specification of a hierarchy of hypercomputers that can hypercompute the truths of all propositions in the standard class model of set theory, the von Neumann hierarchy of pure sets. [ABSTRACT FROM AUTHOR]

Purpose: The objective of this study was to identify and evaluate the value of prognostic factors related to disability, pain and quality of life (QoL) for adult patients undergoing lumbar spine fusion surgery (LSFS). Methods: Two reviewers independently searched the literature, assessed eligibility, extracted data and assessed risk of bias and certainty of evidence. Key electronic databases were searched [PubMed, CINAHL, EMBASE, MEDLINE, PEDro and ZETOC] using pre-defined terms [e.g. LSFS] to 20/9/2020; with additional searching of journals, reference lists and unpublished literature. Prospective cohort studies with ≥ 12-month follow-up after LSFS were included. Narrative synthesis was based on recommendations by Cochrane Consumers and Communication Review Group. The GRADE tool enabled assessment of certainty of evidence. Prognostic factors and outcome were analysed and summarised when examined in ≥ 2 studies and when results pointed in the same direction in ≥ 75% of studies. Results: Sixteen studies (n = 8388, 2 low and 14 high risk of bias) were included with 39 prognostic factors identified. There is low certainty evidence that higher pre-operative severity of leg pain predicts greater improvement of leg pain and that pre-operative working predicts less post-operative disability both at 1–2-year follow-up. Other found associations were of very low certainty evidence. Conclusion: No moderate to high certainty evidence exists. Use of leg pain and pre-operative working may be valuable predictors of outcome to inform clinical decision-making and advice regarding LSFS surgery. There is need for adequately powered low-risk-of-bias prospective observational studies to further investigate candidate prognostic factors. [ABSTRACT FROM AUTHOR]

This study reports on the prospect for the routine use of Quantum Monte Carlo (QMC) for the electronic structure problem, applying fixed-node Diffusion Monte Carlo (DMC) to generate highly accurate Born-Oppenheimer potential energy curves (PECs) for small molecular systems. The singlet ground electronic states of CO and N2 were used as test cases. The PECs obtained by DMC employing multiconfigurational trial wavefunctions were compared with those obtained by conventional high-accuracy electronic structure methods such as multireference configuration interaction and/or the best available empirical spectroscopic curves. The goal was to test whether a straightforward procedure using available QMC codes could be applied robustly and reliably. Results obtained with DMC codes were found to be in close agreement with the benchmark PECs, and the n³ scaling with the number of electrons (compared with n7 or worse for conventional high-accuracy quantum chemistry) could be advantageous depending on the system size. Due to a large pre-factor in the scaling, for the small systems tested here, it is currently still much more computationally intensive to compute PECs with QMC. Nevertheless, QMC algorithms are particularly well-suited to large-scale parallelization and are therefore likely to become more relevant for future massively parallel hardware architectures. [ABSTRACT FROM AUTHOR]

The article describes the Romano-British activity at Crowdhill in Fair Oak, Eastleigh, England during the Late Mesolithic Age, Middle Bronze Age and Late Iron Age. It evaluates archaeological excavations and finds at the site including flints from a Long Blade assemblage, a core tool for a tranchet axe and radiocarbon dates obtained from charred hazelnut shells. Several indicators of the presence of a rural settlement in the vicinity of the site were identified including ditches and pottery.

This comment piece explores the decision in Whittington Hospital NHS Trust v XX [2020] UKSC 14. It argues that despite notable shifts in public policy in respect of the acceptability of surrogacy as a means of family formation in the past twenty years, the Supreme Court has taken a step too far in deciding that foreign commercial surrogacy is as widely socially accepted. This impacts on the reasonableness of any claim for damages in negligence for the costs of commercial surrogacy. It is posited that the issue of whether damages for foreign commercial surrogacy are reasonable or not will be the key battleground in future negligence cases of this type. [ABSTRACT FROM AUTHOR]

Extracellular calcium (Ca2+) and store‐operated Ca2+ entry (SOCE) govern homoeostasis in the mammalian epidermis. Multiple microRNAs (miRNA) also regulate epidermal differentiation, and raised external Ca2+ modulates the expression of several such miRNAs in keratinocytes. However, little is known about the regulation of miR‐184 in keratinocytes or the roles of miR‐184 in keratinocyte differentiation. Here we report that exogenous Ca2+ stimulates miR‐184 expression in primary epidermal keratinocytes and that this occurs in a SOCE‐dependent manner. Levels of miR‐184 were raised by about 30‐fold after exposure to 1.5 mM Ca2+ for 5 days. In contrast, neither phorbol ester nor 1,25‐dihydroxyvitamin D3 had any effect on miR‐184 levels. Pharmacologic and genetic inhibitors of SOCE abrogated Ca2+‐dependent miR‐184 induction by 70% or more. Ectopic miR‐184 inhibited keratinocyte proliferation and led to a fourfold increase in the expression of involucrin, a marker of early keratinocyte differentiation. Exogenous miR‐184 also triggered a threefold rise in levels of cyclin E and doubled the levels of γH2AX, a marker of DNA double‐strand breaks. The p21 cyclin‐dependent kinase inhibitor, which supports keratinocyte growth arrest, was also induced by miR‐184. Together our findings point to an SOCE:miR‐184 pathway that targets a cyclin E/DNA damage regulatory node to facilitate keratinocyte differentiation. [ABSTRACT FROM AUTHOR]

A radiocarbon date of cal AD 410-620 obtained from near the base of the substantial ditch defining Ampress Camp, suggests that this riverside enclosure to the north of Lymington, which lay immediately east of the Iron Age hillfort of Buckland Rings, may be sub-Roman in date, and possibly associated with the establishment and/or defence of the Jutish province in southern Hampshire. [ABSTRACT FROM AUTHOR]

Background and Purpose: The 5-HT3 receptor is a prototypical member of the Cys-loop ligand-gated ion channel (LGIC) superfamily and an established therapeutic target. In addition to activation via the orthosteric site, receptor function can be modulated by allosteric ligands. We have investigated the pharmacological action of Cl-indole upon the 5-HT3 A receptor and identified that this positive allosteric modulator possesses a novel mechanism of action for LGICs.Experimental Approach: The impact of Cl-indole upon the 5-HT3 receptor was assessed using single cell electrophysiological recordings and [3 H]-granisetron binding in HEK293 cells stably expressing the 5-HT3 receptor.Key Results: Cl-indole failed to evoke 5-HT3 A receptor-mediated responses (up to 30 μM) or display affinity for the [3 H]-granisetron binding site. However, in the presence of Cl-indole, termination of 5-HT application revealed tail currents mediated via the 5-HT3 A receptor that were independent of the preceding 5-HT concentration but were antagonized by the 5-HT3 receptor antagonist, ondansetron. These tail currents were absent in the 5-HT3 AB receptor. Furthermore, the presence of 5-HT revealed a concentration-dependent increase in the affinity of Cl-indole for the orthosteric binding site of the human 5-HT3 A receptor.Conclusions and Implications: Cl-indole acts as both an orthosteric agonist and an allosteric modulator, but the presence of an orthosteric agonist (e.g. 5-HT) is a prerequisite to reveal both actions. Precedent for ago-allosteric action is available, yet the essential additional presence of an orthosteric agonist is now reported for the first time. This widening of the pharmacological mechanisms to modulate LGICs may offer further therapeutic opportunities. [ABSTRACT FROM AUTHOR]

The article reports on the archaeological evaluation followed by strip-map-and-record excavation which found evidence of Late Bronze Age activity at Hatchwood Farm in Farnham Road, Odiham. Discussed is the archaeological works which was granted by the Hart District Council for the development of the housing and a public park site. Also mentioned are the recorded lists of Late Bronze Age findspots and sites in the area such as the socketed axe and an enclosure.

An excavation and watching brief at Abbotts Barton, Winchester, revealed a short section of Roman road, comprising a metalled surface flanked by two ditches 24m apart. This lies almost 200m east of the often presumed line of the Winchester-Silchester Roman road along Worthy Road. However, it lies almost precisely on a line projected between the sections of road excavated outside the Roman town's north gate at Hyde Street, a length of 'ancient causeway' on the west bank of the River Itchen followed by the Nun's Walk (part of the Pilgrims' Way), and the A33 Basingstoke Road which is known to follow the line of the Roman road. Subsequently, in the early/middle Anglo-Saxon period, probably in the 6th/7th century, a settlement was established beside the Roman road, between it and the edge of the River Itchen floodplain, remaining in occupation possibly into the 9th century. The full extent of the settlement is not known, but the exposed area was divided into a southern part containing five sunken-featured buildings, and a northern part containing at least three post-built buildings (and other post-built structures) and a further sunken-featured building. One sunken-featured building contained large numbers of ceramic loomweights associated with evidence of burning, possibly of floor timbers and a loom. [ABSTRACT FROM AUTHOR]

Prenatal diagnosis of congenital disease improves clinical outcomes; however, as many as 50% of congenital heart disease cases are missed by current ultrasound screening methods. This indicates a need for improved screening technology. Extracellular vesicles (EVs) have attracted enormous interest in recent years for their potential in diagnostics. EVs mediate endocrine signalling in health and disease and are known to regulate aspects of embryonic development. Here, we critically evaluate recent evidence suggesting that EVs released from the foetus are able to cross the placenta and enter the maternal circulation. Furthermore, EVs from the mother appear to be transported in the reverse direction, whilst the placenta itself acts as a source of EVs. Experimental work utilising rodent models employing either transgenically encoded reporters or application of fluorescent tracking dyes provide convincing evidence of foetal-maternal crosstalk. This is supported by clinical data demonstrating expression of placental-origin EVs in maternal blood, as well as limited evidence for the presence of foetal-origin EVs. Together, this work raises the possibility that foetal EVs present in maternal blood could be used for the diagnosis of congenital disease. We discuss the challenges faced by researchers in translating these basic science findings into a clinical non-invasive prenatal test. [ABSTRACT FROM AUTHOR]

Intellectual disability affects 2–3% of the population; mutations of the X-chromosome are a major cause of moderate to severe cases. The link between the molecular consequences of the mutation and impaired cognitive function remains unclear. Loss of function mutations of oligophrenin-1 (OPHN1) disrupt Rho-GTPase signalling. Here we demonstrate abnormal neurotransmission at CA3 synapses in hippocampal slices from Ophn1-/y mice, resulting from a substantial decrease in the readily releasable pool of vesicles. As a result, synaptic transmission fails at high frequencies required for oscillations associated with cognitive functions. Both spontaneous and KA-induced gamma oscillations were reduced in Ophn1-/y hippocampal slices. Spontaneous oscillations were rapidly rescued by inhibition of the downstream signalling pathway of oligophrenin-1. These findings suggest that the intellectual disability due to mutations of oligophrenin-1 results from a synaptopathy and consequent network malfunction, providing a plausible mechanism for the learning disabilities. Furthermore, they raise the prospect of drug treatments for affected individuals. [ABSTRACT FROM AUTHOR]

An ethylene propylene rubber polyampholyte (EPR-g-PA) containing zwitterionic ammonium carboxylate grafts is prepared by reacting maleated EPR (EPR-g-MAn) with a tertiary amino alcohol, 2-[2-(dimethylamino)ethoxy]ethanol (DMAEE). EPR-g-PA has equivalent viscoelastic properties to an EPR that is lightly cross-linked using a peroxide cure, but with a higher strain hardening coefficient and elongation at break. EPR-g-PA has similar adhesion to metals and improved adhesion to other ionomers, whereas the adhesive strength to a polyamide substrate is reduced compared to the EPR-g-MAn. The in situ reaction of EPR-g-MAn with DMAEE during blending with PP produced a blend with superior impact properties compared to the thermoplastic vulcanizate (TPV) blend of peroxide cross-linked EPR-g-MAn and PP. [ABSTRACT FROM AUTHOR]

To develop and validate a non-contrast free-breathing whole-heart 3D cine steady-state free precession (SSFP) sequence with a novel 3D radial leaf trajectory. We used a respiratory navigator to trigger acquisition of 3D cine data at end-expiration to minimize respiratory motion in our 3D cine SSFP sequence. We developed a novel 3D radial leaf trajectory to reduce gradient jumps and associated eddy-current artifacts. We then reconstructed the 3D cine images with a resolution of 2.0mm3 using an iterative nonlinear optimization algorithm. Prospective validation was performed by comparing ventricular volumetric measurements from a conventional breath-hold 2D cine ventricular short-axis stack against the non-contrast free-breathing whole-heart 3D cine dataset in each patient (n = 13). All 3D cine SSFP acquisitions were successful and mean scan time was 07:09 ± 01:31 min. End-diastolic ventricular volumes for left ventricle (LV) and right ventricle (RV) measured from the 3D datasets were smaller than those from 2D (LV: 159.99 ± 42.99 vs. 173.16 ± 47.42; RV: 180.35 ± 46.08 vs. 193.13 ± 49.38; p -value≤0.044; bias<8%), whereas ventricular end-systolic volumes were more comparable (LV: 79.12 ± 26.78 vs. 78.46 ± 25.35; RV: 97.18 ± 32.35 vs. 102.42 ± 32.53; p-value≥0.190, bias<6%). The 3D cine data had a lower subjective image quality score. Our non-contrast free-breathing whole-heart 3D cine sequence with novel leaf trajectory was robust and yielded smaller ventricular end-diastolic volumes compared to 2D cine imaging. It has the potential to make examinations easier and more comfortable for patients. [ABSTRACT FROM AUTHOR]

Non-technical summary Intellectual disability has long been attributed at the cellular level to abnormalities in the structures that receive incoming connections to the major classes of neurons in the brain. These misshaped 'dendrites' and especially misshaped 'dendritic spines' have been found in many types of intellectual disability. We have used a mouse model of one of the human intellectual disability mutations on a gene on the X-chromosome called Ophn-1. We show that, in addition to the misshaped dendritic spines, these mice have abnormal physiology in the inability of both excitatory and inhibitory inputs ('synapses') to operate repetitively as they need to in many aspects of normal brain function. A drug known as a Rho-GAP inhibitor was able to reverse the physiological impairment within 20 min, without changing the structure of dendrites or dendritic spines. This class of drug may have a role in limiting disability in this condition. [ABSTRACT FROM AUTHOR]

Abstract: Particle identification in the LHCb experiment is provided by two RICH detectors, covering a momentum range of approximately 1–100GeV/c. To maintain the integrity of the LHCb physics performance, it is essential to measure and monitor the particle identification efficiency and misidentification fraction over time. To achieve this, the unique decay kinematics associated with K S 0, and decays are exploited to obtain high purity samples of pions, protons and kaons through the use of tracking information alone. Such calibration samples then allow for an unbiased assessment of the performance of the RICH detectors. Given the high production rates of K S 0, and mesons at the LHC, monitoring of the RICH detectors performance is possible both “on-line” during running and “off-line” after full-reconstruction of the data. Following analysis of the first LHC collisions, the performance of the LHCb RICH detectors will be presented based on a preliminary alignment of the detector. Identification and mis-identification probabilities as a function of track momentum will be shown. [Copyright &y& Elsevier]

Spirituality is inherent in human consciousness. As ego strivings of the first half of life give way to the need to find a deeper and enduring sense of meaning and purpose, big questions about life loom large, not least when we fall ill and experience the frailty of human existence. It is the privilege of healthcare professionals aware of the desire for healing for which every human soul yearns, to be able to help patients find a new sense of wholeness in times of adversity. [ABSTRACT FROM AUTHOR]

Spirituality is assuming increasing importance in clinical practice and in research in psychiatry. This increasing salience of spirituality raises important questions about the boundaries of good professional practice. Answers to these questions require not only careful attention to defining and understanding the nature of spirituality, but also closer attention to the nature of concepts of secularity and self than psychiatry has usually given. Far from being 'neutral ground,' secularity is inherently biased against concepts of transcendence. Our secular age is preoccupied with a form of immanence that emphasises interiority, autonomy and reason, but this preoccupation has paradoxically been associated with an explosion of interest in the transcendent in new, often non-religious and non-traditional forms. This context, as well as the increasing evidence base for spiritual and religious coping as important ways of dealing with mental stress and mental disorder, requires that psychiatry gives more careful attention to the ways in which people find meaning in spirituality and religion. This in turn requires that more clinical attention be routinely given to spiritual history taking and the incorporation of spiritual considerations in treatment planning. [ABSTRACT FROM AUTHOR]

Brain stimulation is currently used as an experimental treatment for patients with medically refractory epilepsy. However, the results of such stimulation are still less than optimal. A major factor is the lack of understanding of the mechanisms of applied stimuli. Herein we review evidence on the effects of stimulation in models of epileptic seizures. We show that the effects of stimulation during epileptic seizures can differ from those observed under normal conditions. Several studies suggest a potentially greater beneficial therapeutic effect of strong depolarizing and overactivating stimulations than hyperpolarizing ones in the treatment of seizures. The potential relevance of these results to other therapeutic stimulation protocols is discussed. [ABSTRACT FROM AUTHOR]

The author offers a commentary on the South Carolina Business Court Pilot Program. He explores the goals, history, structure, and initial results of the program. He analyzes the advantages and disadvantages of the program to the state's judiciary and business climate. Delaware's Court of Chancery and the North Carolina Business Court, which are considered two of the most successful courts specializing in business, are discussed. Proposed changes to the pilot program are also offered.

Objectives: This study sought to examine the prevalence and predictors of pulmonary regurgitation (PR) following balloon dilation (BD) for pulmonary stenosis (PS) and to investigate its impact on ventricular volume and function, and exercise tolerance. Background: Balloon pulmonary valvuloplasty relieves PS but can cause late PR. The sequelae of isolated PR are not well understood. Methods: Patients were at least 7 years of age and 5 years removed from BD, and had no other form of congenital heart disease or significant residual PS. Cardiac magnetic resonance imaging and exercise testing were performed prospectively to quantify PR fraction, ventricular volumes and function, and exercise capacity. Results: Forty-one patients underwent testing a median of 13.1 years after BD. The median PR fraction was 10%; 14 patients (34%) had PR fraction >15%; 7 (17%) had PR >30%. PR fraction was associated with age at dilation (ln-transformed, R = −0.47, p = 0.002) and balloon:annulus ratio (R = 0.57, p < 0.001). The mean right ventricular (RV) end-diastolic volume z-score was 1.8 ± 1.9; RV dilation (z-score ≥2) was present in 14/35 patients (40%). PR fraction correlated closely with indexed RV end-diastolic volume (R = 0.79, p < 0.001) and modestly with RV ejection fraction (R = 0.50, p < 0.001). Overall, peak oxygen consumption (Vo 2) (% predicted) was below average (92 ± 17%, p = 0.006). Patients with PR fraction >15% had significantly lower peak Vo 2 than those with less PR (85 ± 17% vs. 96 ± 16%, p = 0.03). Conclusions: Mild PR and RV dilation are common in the long term following BD. A PR fraction >15% is associated with lower peak Vo 2, suggesting that isolated PR and consequent RV dilation are related to impaired exercise cardiopulmonary function. [Copyright &y& Elsevier]

Summary: High-frequency electrographic activity (HFA) has a frequency of 80–600Hz. It can be observed interictally in epileptic foci and also at the onset of epileptic seizures. There are several hypotheses about how HFA is generated, and it has been suggested that the underlying mechanisms may play an important role in epileptogenesis and ictogenesis. The high specificity of HFA for epileptic foci is now used during presurgical evaluation to help localize epileptic focus. In this article we review the current state of knowledge regarding this phenomenon and challenges for the future studies focusing on HFA. [Copyright &y& Elsevier]

Abstract: Patients with functional single ventricle heart disease undergo a series of palliative surgeries, typically culminating in a Fontan-type circulation. For the past three decades, the primary cardiac imaging modalities used to follow such patients have been echocardiography and catheter angiography. With the advent and rapid development of cardiac magnetic resonance and cardiac computed tomography over the past decade, these modalities offer novel techniques and capabilities to evaluate the single ventricle circulation. This article reviews the surgical management of the patient with functional single ventricle, and then explores the role of various imaging modalities in this setting with an emphasis on these newer techniques. [Copyright &y& Elsevier]

Abstract: P2X receptors are a distinct family of ATP-gated ion channels with a number of physiological roles ranging from smooth muscle contractility to the regulation of blood clotting. In this study we determined whether the UV light-reactive ATP analogues 2-azido ATP, ATP azidoanilide (ATP-AA) and 2′,3′-O-(4-benzoylbenzoyl)-ATP (BzATP) can be used to label the ATP binding site of P2X1 receptors. These analogues were agonists, and in patch clamp studies evoked inward currents from HEK293 cells stably expressing the P2X1 receptor. Following irradiation in the presence of these compounds subsequent responses to an EC50 concentration of ATP were reduced by >65%. These effects were partially reversed by co-application of ATP or suramin with the photo-reactive ATP analogue at the time of irradiation. In autoradiographic studies radiolabelled 2-azido [γ32P] ATP and ATP-AA-[γ32P] cross-linked to P2X1 receptors and this binding was reduced by co-incubation with ATP. These studies demonstrate that photo-reactive ATP analogues can be used to label P2X receptor and may prove useful in elucidating the ATP binding site at this novel class of ATP binding proteins. [Copyright &y& Elsevier]

Prion protein (PrP) is a normal component of neurons, which confers susceptibility to prion diseases. Despite its evolutionary conservation, its normal function remains controversial. PrP-deficient (Prnp0/0) mice have weaker afterhyperpolarizations (AHPs) in cerebellar and hippocampal neurons. Here we show that the AHP impairment in hippocampal CA1 pyramidal cells is selective for the slow AHP, and is not caused by an impairment of either voltage-gated Ca2+ channels or Ca2+-activated K+ channels. Instead, Prnp0/0 neurons have twofold to threefold stronger Ca2+ buffering and double the Ca2+ extrusion rate. In Prnp0/0 neurons thapsigargin abolished the stronger Ca2+ buffering and extrusion, and thapsigargin or cyclopiazonic acid abolished the weakening of the slow AHPs. These data implicate sarcoplasmic/endoplasmic reticulum calcium ATPase in the enhanced Ca2+ buffering, and extrusion into the endoplasmic reticulum, which contains substantial amounts of PrP in wild-type mice. Altered Ca2+ homeostasis can explain several phenotypes identified in Prnp0/0 mice. [ABSTRACT FROM AUTHOR]

Objective exercise testing in patients with repaired tetralogy of Fallot frequently identifies gross deficiencies in exercise capacity. These findings are typically attributed to right ventricular dysfunction, pulmonary valve regurgitation, and pulmonary artery stenosis and are used to justify referrals for surgical or transcatheter interventions. However, the relation between right-sided cardiac abnormalities and exercise capacity in this patient group is poorly understood. Cardiac magnetic resonance imaging correlates of exercise capacity in 37 patients with repaired TOF were retrospectively examined. In conclusion, on multivariate analysis, right ventricular ejection fraction was the only cardiac magnetic resonance imaging predictor of percentage of predicted peak oxygen consumption, oxygen consumption at ventilatory anaerobic threshold, and oxygen pulse. [Copyright &y& Elsevier]

The sensitivity of brain tissue to weak extracellular electric fields is important in assessing potential public health risks of extremely low frequency (ELF) fields, and potential roles of endogenous fields in brain function. Here we determine the effect of applied electric fields on membrane potentials and coherent network oscillations. Applied DC electric fields change transmembrane potentials in CA3 pyramidal cell somata by 0.18 mV per V m−1 applied. AC sinusoidal electric fields have smaller effects on transmembrane potentials: sensitivity drops as an exponential decay function of frequency. At 50 and 60 Hz it is ∼0.4 that for DC fields. Effects of fields of ≤ 16 V m−1 peak-to-peak (p-p) did not outlast application. Kainic acid (100 nm) induced coherent network oscillations in the beta and gamma bands (15–100 Hz). Applied fields of ≥ 6 V m−1 p-p (2.1 V m−1 r.m.s.) shifted the gamma peak in the power spectrum to centre on the applied field frequency or a subharmonic. Statistically significant effects on the timing of pyramidal cell firing within the oscillation appeared at distinct thresholds: at 50 Hz, 1 V m−1 p-p (354 mV m−1 r.m.s.) had statistically significant effects in 71% of slices, and 0.5 V m−1 p-p (177 mV m−1 r.m.s.) in 20%. These threshold fields are consistent with current environmental guidelines. They correspond to changes in somatic potential of ∼70 μV, below membrane potential noise levels for neurons, demonstrating the emergent properties of neuronal networks can be more sensitive than measurable effects in single neurons. [ABSTRACT FROM AUTHOR]

Abstract: Exocytosis of neurotransmitter is initiated by formation of a fusion pore, a narrow channel connecting the vesicle lumen to the extracellular space. Opening of the fusion pore can produce a flow of capacitative current, which was used to resolve the exocytosis of mast cell giant secretory granules by Breckenridge and Almers [Breckenridge LJ, Almers W. Currents through the fusion pore that forms during exocytosis of a secretory vesicle. Nature 1987;328:814–7]. We present an extension of this method to resolve fusion pore formation initiating exocytosis of single vesicles in bovine chromaffin cells. Cell-attached patch recordings revealed a capacitative current that was evoked by an increase of intracellular calcium (Ca2+) from application of a Ca2+ ionophore or by the opening of a co-localized Ca2+ channel. Calculated values for fusion pore conductance and vesicular membrane potential were in accord with previous estimates. Finally, we show that a single opening of a co-localized calcium channel evoked fusion pore formation, with delay times between channel opening and exocytosis agreeing with other methods. This method can be applied to resolve exocytosis regardless of what the vesicle contains or where exocytosis occurs, giving the possibility of using this method to resolve the release of synaptic vesicles. [Copyright &y& Elsevier]

Cardiac magnetic resonance imaging (CMR) has become integrated into the routine care of individuals with congenital heart disease. Its strengths and limitations are being refined and CMR derived variables predictive of clinically important outcomes are being evaluated. This manuscript will focus on several congenital heart diseases commonly referred for CMR evaluation and review their clinical aspects, goals of the MRI evaluation, imaging protocol and current literature. [ABSTRACT FROM AUTHOR]

Cardiac magnetic resonance imaging (CMR) can provide comprehensive anatomic and physiological information about the cardiovascular system. The review article describes the application of CMR to several simple congenital heart lesions: atrial septal defects and other interatrial communications, ventricular septal defects, patent ductus arteriosus, partially anomalous pulmonary venous connection, and coarctation of the aorta. The anatomy, clinical features, and management of these lesions are discussed. CMR techniques to evaluate patients with these lesions are described and relevant literature is reviewed. [ABSTRACT FROM AUTHOR]

Objectives: Carbon Monoxide (CO), the third most common cause of acute poisoning death, is easily overlooked in the emergency department (ED). Nonspecific complaints such as headache, weakness, or malaise may easily result in misdiagnosis. The objectives of this study are to determine the frequency of CO poisoning in patients presenting to the ED complaining of headaches and determine the feasibility of using noninvasive CO analyzers as a screening tool. Methods: This prospective controlled study examined, during the winter months, adult patients presenting with a complaint of atraumatic, afebrile headaches. All subjects submitted a sample for a CO breath analyzer. Participants with elevated carboxyhemoglobin (COHb) levels (nonsmokers <2%, smokers <5%) underwent venous COHb testing. Control patients, without headaches, presenting to the ED were similarly studied. Results: We enrolled 170 subjects and 98 controls. Of the 170 subjects, 12 (7.1%) had elevated COHb levels confirmed by venous COHb levels. Of the 98 controls, 1 (1.0%) had an elevated COHb level (p < 0.05). There were no differences in demographic factors between the two groups (p < 0.16). Conclusions: Noninvasive measurement of CO levels in ED patients with headaches is rapid and specific. During winter months, elevated CO levels are present in over 7% of ED patients with headaches. [ABSTRACT FROM AUTHOR]

This paper describes a new and simple microarray platform for presenting multiple nonderivatized oligosaccharides to protein targets, with utility for mapping carbohydrate—protein recognition events. The approach is based on the creation of a hydrazide-derivatized, self-assembled monolayer on a gold surface in a single or two-step procedure, for efficient and selectively oriented anchoring of oligosaccharide probes via their reducing ends, with detection using fluorescence detection of bound proteins. The biggest hurdles in employing gold-based substrate for fluorescence-based microarray detection include fluorescence quenching and nonspecific surface adsorption of proteins. We found that the quenching effect could be minimized by introducing a ω-thiolated fatty acid (C16) self-assembled monolayer between the gold surface and hydrazide groups, followed by detection involving three successive binding protein layers covering the gold surface. In addition, an effective blocking scheme involving poly(ethylene glycol) aldehyde and bovine serum albumin was employed to reduce nonspecific protein adsorption to the chip surface. As proof of principle, we demonstrate here that sulfated oligosaccharide probes from heparin can be effectively and covalenfly attached without prior derivatization onto the hydrazide-modified, self-assembled monolayer on gold-coated slide surfaces in a microarray format. This platform is used to assess binding of specific heparin-binding protein targets at very high sensitivity, and we also demonstrate that the approach can be extended to nonsulfated sugars. Direct attachment of nonderivatized sugar probes on the chip is advantageous since it avoids the need for laborious prederivatization and cleanup steps. This versatile fluorescence microarray platform provides a facile approach for interrogating multiple carbohydrate-protein interactions in a high-throughput manner and has potential as a common gold surface platform for other diverse interrogations by MALDI-MS, surface plasmon resonance, and quartz crystal microbalances. [ABSTRACT FROM AUTHOR]

We present a model that encompasses three distinct motives for dollarization (price volatility, credit risk, and moral hazard) and discuss when risk‐based prudential policy responses are called for and the form they should take. We argue that the overall policy response must be tailored to the nature of the dollarization the economy is facing. However, prudential policies should be formulated irrespective of the roots of dollarization. Their aim should be to enhance financial stability by ensuring that banks internalize credit risk within acceptable risk tolerance levels, taking dollarization and the current monetary policy environment as given. [ABSTRACT FROM AUTHOR]

The significant rise in foreign bank claims observed during the 1990s, following their steep decline during the 1980s debt crisis, reignited interest in understanding the behavior of these flows. This paper analyzes changes in foreign bank claims on the Latin American private sector over the period 1985-2000. We find that banks transmit shocks from their home countries (where banks' headquarters are located) and that changes in claims on individual host countries (those that receive claims) are correlated with aggregate changes in claims on other countries. However, over time, we observe that foreign bank claims have become less responsive to external factors. Also, we present evidence that the sensitivity of foreign bank claims to host factors diminishes, as banks' aggregate exposure rises. Finally, we find that foreign bank claims react more to positive than to negative host shocks and are not significantly curtailed during crises. [ABSTRACT FROM AUTHOR]

The Neolithic court tombs of Ireland display variation in the ways that their component parts - concave courts, linear galleries and individual cells - were combined and arranged. This variation has been interpreted in the past in terms of both the diffusion of ideas and the design requirements of their builders. In this article it is suggested that the analysis of these formalized components points to central themes of the social and ritual discourse that accompanied the tombs' construction and use, the symbolism of the tombs expressing alleged lineage relationships between the living community, its ancestors and the land. It is suggested that these communities were based on one or more corporate descent groups, in some cases combining with other social units to appropriate and exploit territory, the relationships between them being symbolized and idealized in the spatial layout of the tombs' orthostatic structures. [ABSTRACT FROM AUTHOR]

This study examined the effects of endovascular metallic implants on the ability of magnetic resonance imaging to evaluate cardiovascular anatomy and to assess ventricular size and function in 101 consecutive patients with Fontan palliation. Compared with studies in patients without implants, in whom 100% of anatomic segments were adequately visualized and the median image quality grade for ventricular function assessment was 5 of 5, the presence of any implant (54% of studies) reduced the proportion of adequately imaged anatomy to 77% (p &#60;0.001) and the median image quality grade for ventricular function assessment to 3 of 5 (p &#60;0.001). [Copyright &y& Elsevier]

The nociceptive C-fibers of the dorsal root ganglion express several sodium channel isoforms that associate with one or more regulatory β-subunits (β1–β4). To determine the effects of individual and combinations of the β-subunit isoforms, we co-expressed Nav1.8 in combination with these β-subunits in Xenopus oocytes. Whole-cell inward sodium currents were recorded using the two-microelectrode voltage clamp method. Our studies revealed that the co-expression β1 alone or in combination with other β-subunits enhanced current amplitudes, accelerated current decay kinetics, and negatively shifted the steady-state curves. In contrast, β2 alone and in combination with β1 altered steady-state inactivation of Nav1.8 to more depolarized potentials. Co-expression of β3 shifted steady-state inactivation to more depolarized potentials; however, combined β1β3 expression caused no shift in channel availability. The results in this study suggest that the functional behavior of Nav1.8 will vary depending on the type of β-subunit that expressed under normal and disease states. [Copyright &y& Elsevier]

This study examined the feasibility and potential clinical utility of magnetic resonance imaging (MRI) evaluation of myocardial perfusion (first-pass contrast enhancement) and viability (myocardial delayed enhancement) in 30 patients with congenital and acquired pediatric heart disease. Good agreement was found between MRI evaluation of myocardial perfusion and viability and analysis of segmental wall motion as well as coronary angiography (n = 10) and single photon emission computed tomography (n = 6). [Copyright &y& Elsevier]

: ObjectivesThe goal of this study was to evaluate the diagnostic value of gadolinium (Gd)-enhanced three-dimensional (3D) magnetic resonance angiography (MRA) in patients with congenital and acquired anomalies of the pulmonary and systemic veins.: BackgroundGadolinium-enhanced 3D MRA is a fast magnetic resonance imaging technique that has shown great promise in the evaluation of large and medium-sized arteries. However, its application to venous anomalies has not been studied in detail.: MethodsThe study retrospectively analyzed all patients who underwent Gd-enhanced 3D MRA examination from January 1998 through January 2001, were diagnosed with anomalies of the pulmonary or systemic veins and had additional diagnostic data available for comparison with the MRA findings.: ResultsSixty-one patients (age 1 day to 60 years) were included. Image acquisition was completed in 29 ± 6.9 s. Pulmonary venous anomalies were found in 37 patients, systemic venous anomalies in 17 patients and both pulmonary and systemic venous anomalies in 7 patients. Compared with available diagnostic information by other modalities, all known or suspected venous anomalies were imaged by 3D MRA. In three patients, catheterization did not detect anomalies of the pulmonary veins that were subsequently diagnosed by MRA. The 3D MRA diagnoses were followed by 10 interventional catheterization procedures and 15 operations. In 74% of patients, 3D MRA either diagnosed previously unsuspected venous anomalies (28%) or added new clinically important information (46%). The mechanism of pulmonary vein compression in eight patients was determined by MRA but not by other imaging modalities. Using a five-level grading system for MRA image quality (1 = nondiagnostic; 5 = excellent), the average grade was 4.6 ± 0.6, with a 0.28 ± 0.6 mean grade difference between two independent observers.: ConclusionsGadolinium-enhanced 3D MRA is capable of rapidly and accurately diagnosing a wide spectrum of pulmonary and systemic venous anomalies and is a useful noninvasive alternative to diagnostic catheterization. [Copyright &y& Elsevier]

Studies the perioperative risk factors for development of protein-losing enteropathy following a Fontan procedure. Estimated probability of freedom from protein-losing enteropathy after the Fontan procedure; Analysis of risk factors for time to protein-losing enteropathy.

SUMMARY1. Intracellular microelectrodes were used to record spontaneous and evoked inhibitory junction potentials (IJP) from the circular muscle layer of the mid-distal region of the mouse isolated colon in the presence of nifedipine (1 μmol/L) and hyoscine (1 μmol/L). 2. The length of the tissue preparation (> 1 cm) or the presence of the mucosa had no effect on the frequency of spontaneous IJP. 3. Hexamethonium (500 μmol/L) reduced the frequency of spontaneous IJP to approximately 70% of the control frequency, whereas D-tubocurarine (280 μmol/L) reduced the frequency to approximately 17% of control. Apamin (250 nmol/L) abolished all spontaneous IJP activity. 4. The greater inhibition of spontaneous IJP in the presence of D-tubocurarine compared with hexamethonium is discussed as a possible ‘apamin-like’ effect. 5. Although electrically evoked IJP (single pulse at 15 V, 0.6 msec) were not significantly affected by hexamethonium, D-tubocurarine and apamin reduced the amplitude of evoked IJP to approximately 65 and 50% of control, respectively. 6. These results suggest that the properties of spontaneous IJP cannot be inferred by a study of evoked IJP alone. [ABSTRACT FROM AUTHOR]

Management of all patients with pulmonary atresia, intact ventricular septum, and right ventricle-dependent coronary circulation (n = 12) with staged surgery directed toward a Fontan palliation resulted in an 83% 5-year actuarial survival. Both deaths in the study were presumably related to coronary ischemia and occurred in the first 4 months of life. [ABSTRACT FROM AUTHOR]