Off-line learning in a rhythmic bimanual task: early feedback dependency is reduced over wakefulness.

Research has supported two distinct forms of motor skill consolidation that can occur between practice sessions: (1) off-line learning, and (2) memory stabilization. Off-line learning describes performance improvement between practice sessions that is above the gain observed at the end of practice, while memory stabilization describes a gain in performance that is maintained between practice sessions. This study used a Lissajous plot to provide concurrent feedback to train participants to produce a 90° relative phase between the index fingers (flexion/extension motion). Significant improvements in performance emerged after ten trials (5 min) of practice. At the end of training, participants were divided into two delay interval groups before retesting, 2-h and 6-h. The retesting session started with participants performing an interference task (10 trials, 5 min) that required training on a 45° relative phase between the fingers with concurrent feedback from the Lissajous plot. When training with the interference task was completed participants were retested with the 90° relative phase without the Lissajous plot feedback. In the retest of the 90° pattern, a performance loss was found in the 2-h delay group, whereas the 6-h delay group maintained the end of practice performance level. Maintenance of the same level of performance without the Lissajous plot represents memory stabilization of the initially trained 90° pattern. The findings are discussed within the context of current positions regarding procedural consolidation and the coordination dynamics framework wherein action and perception are linked through the informational nature of relative phase.

The addition of insulin to home parenteral nutrition for the control of hyperglycaemia: A case series.

There is little data on the safety or efficacy of insulin added to parenteral nutrition in the homecare setting. We report the use of this route of insulin administration in a series of 4 patients spanning 39 patient years in which it appeared effective, safe and well tolerated.

An Iterative Diffeomorphic Algorithm for Registration of Subdivision Surfaces: Application to Congenital Heart Disease.

In this paper, we present a new diffeomorphic registration algorithm for the registration of 3D models to 3D points. A biventricular template is iteratively fitted to the data by a series of implicitly constrained diffeomorphic linear least squares fits with decreasing regularization weights before performing an explicitly constrained diffeomorphic fit. The algorithm has been tested on a set of manual contours from 20 patients with a variety of congenital heart disease. Registration accuracy was assessed by calculating the mean point-to-point distance and the Dice overlap metric. Results showed that the method was able to accurately fit the biventricular model to 3D points and that the deformable model was able to fit all the pathologies while being diffeomorphic. The algorithm took approximately 5 minutes to fit each case, with an average of 52,580 points per case.

Spanish and Catalan translation, cultural adaptation and validation of the Picker Patient Experience Questionnaire-15.

OBJECTIVE: To develop and test a culturally adapted core set of questions to measure patients' experience after in-patient care. MATERIAL AND METHODS: Following the methodology recommended by international guides, a basic set of patient experience questions, selected from Picker Institute Europe questionnaires (originally in English), was translated to Spanish and Catalan. Acceptability, construct validity and reliability of the adapted questionnaire were assessed via a cross-sectional validation study. The inclusion criteria were patients aged >18 years, discharged within one week to one month prior to questionnaire sending and whose email was available. Day cases, emergency department patients and deaths were excluded. Invitations were sent by email (N=876) and questionnaire was fulfilled through an online platform. An automatic reminder was sent 5 days later to non-respondents. RESULTS: A questionnaire, in Spanish and Catalan, with adequate conceptual and linguistic equivalence was obtained. Response rate was 44.4% (389 responses). The correlation matrix was factorable. Four factors were extracted with Parallel Analysis, which explained 43% of the total variance. First factor: information and communication received during discharge. Second factor: low sensitivity attitudes of professionals. Third factor: assessment of communication of medical and nursing staff. Fourth factor: global items. The value of the Cronbach alpha was 0.84, showing a high internal consistency. CONCLUSIONS: The obtained experience patient questionnaire, in Spanish and Catalan, shows good results in the psychometric properties evaluated and could be a useful tool to identify opportunities for health care improvement in our context. Email could become a feasible tool for greater patient participation in everything that concerns his health.

Suppression of Emittance Growth Using a Shaped Cold Atom Electron and Ion Source.

We demonstrate precise control of charged particle bunch shape with a cold atom electron and ion source to create bunches with linear and, therefore, reversible Coulomb expansion. Using ultracold charged particles enables detailed observation of space-charge effects without loss of information from thermal diffusion, unambiguously demonstrating that shaping in three dimensions can result in a marked reduction of Coulomb-driven emittance growth. We show that the emittance growth suppression is accompanied by an increase in bunch focusability and brightness, improvements necessary for the development of sources capable of coherent single-shot ultrafast electron diffraction of noncrystalline objects, with applications ranging from femtosecond chemistry to materials science and rational drug design.

Caveolae in ventricular myocytes are required for stretch-dependent conduction slowing.

Mechanical stretch of cardiac muscle modulates action potential propagation velocity, causing potentially arrhythmogenic conduction slowing. The mechanisms by which stretch alters cardiac conduction remain unknown, but previous studies suggest that stretch can affect the conformation of caveolae in myocytes and other cell types. We tested the hypothesis that slowing of action potential conduction due to cardiac myocyte stretch is dependent on caveolae. Cardiac action potential propagation velocities, measured by optical mapping in isolated mouse hearts and in micropatterned mouse cardiomyocyte cultures, decreased reversibly with volume loading or stretch, respectively (by 19±5% and 26±4%). Stretch-dependent conduction slowing was not altered by stretch-activated channel blockade with gadolinium or by GsMTx-4 peptide, but was inhibited when caveolae were disrupted via genetic deletion of caveolin-3 (Cav3 KO) or membrane cholesterol depletion by methyl-ß-cyclodextrin. In wild-type mouse hearts, stretch coincided with recruitment of caveolae to the sarcolemma, as observed by electron microscopy. In myocytes from wild-type but not Cav3 KO mice, stretch significantly increased cell membrane capacitance (by 98±64%), electrical time constant (by 285±149%), and lipid recruitment to the bilayer (by 84±39%). Recruitment of caveolae to the sarcolemma during physiologic cardiomyocyte stretch slows ventricular action potential propagation by increasing cell membrane capacitance.

Detailed observation of space-charge dynamics using ultracold ion bunches.

Control of Coulomb expansion in charged particle beams is of critical importance for applications including electron and ion microscopy, injectors for particle accelerators and in ultrafast electron diffraction, where space-charge effects constrain the temporal and spatial imaging resolution. The development of techniques to reverse space-charge-driven expansion, or to observe shock waves and other striking phenomena, have been limited by the masking effect of thermal diffusion. Here we show that ultracold ion bunches extracted from laser-cooled atoms can be used to observe the effects of self-interactions with unprecedented detail. We generate arrays of small closely spaced ion bunches that interact to form complex and surprising patterns. We also show that nanosecond cold ion bunches provide data for analogous ultrafast electron systems, where the dynamics occur on timescales too short for detailed observation. In a surprising twist, slow atoms may underpin progress in high-energy and ultrafast physics.

A novel computational model of mouse myocyte electrophysiology to assess the synergy between Na+ loading and CaMKII.

Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) hyperactivity in heart failure causes intracellular Na(+) ([Na(+)]i) loading (at least in part by enhancing the late Na(+) current). This [Na(+)]i gain promotes intracellular Ca(2+) ([Ca(2+)]i) overload by altering the equilibrium of the Na(+)-Ca(2+) exchanger to impair forward-mode (Ca(2+) extrusion), and favour reverse-mode (Ca(2+) influx) exchange. In turn, this Ca(2+) overload would be expected to further activate CaMKII and thereby form a pathological positive feedback loop of ever-increasing CaMKII activity, [Na(+)]i, and [Ca(2+)]i. We developed an ionic model of the mouse ventricular myocyte to interrogate this potentially arrhythmogenic positive feedback in both control conditions and when CaMKIIδC is overexpressed as in genetically engineered mice. In control conditions, simulation of increased [Na(+)]i causes the expected increases in [Ca(2+)]i, CaMKII activity, and target phosphorylation, which degenerate into unstable Ca(2+) handling and electrophysiology at high [Na(+)]i gain. Notably, clamping CaMKII activity to basal levels ameliorates but does not completely offset this outcome, suggesting that the increase in [Ca(2+)]i per se plays an important role. The effect of this CaMKII-Na(+)-Ca(2+)-CaMKII feedback is more striking in CaMKIIδC overexpression, where high [Na(+)]i causes delayed afterdepolarizations, which can be prevented by imposing low [Na(+)]i, or clamping CaMKII phosphorylation of L-type Ca(2+) channels, ryanodine receptors and phospholamban to basal levels. In this setting, Na(+) loading fuels a vicious loop whereby increased CaMKII activation perturbs Ca(2+) and membrane potential homeostasis. High [Na(+)]i is also required to produce instability when CaMKII is further activated by increased Ca(2+) loading due to ß-adrenergic activation. Our results support recent experimental findings of a synergistic interaction between perturbed Na(+) fluxes and CaMKII, and suggest that pharmacological inhibition of intracellular Na(+) loading can contribute to normalizing Ca(2+) and membrane potential dynamics in heart failure.

Improved discretisation and linearisation of active tension in strongly coupled cardiac electro-mechanics simulations.

Mathematical models of cardiac electro-mechanics typically consist of three tightly coupled parts: systems of ordinary differential equations describing electro-chemical reactions and cross-bridge dynamics in the muscle cells, a system of partial differential equations modelling the propagation of the electrical activation through the tissue and a nonlinear elasticity problem describing the mechanical deformations of the heart muscle. The complexity of the mathematical model motivates numerical methods based on operator splitting, but simple explicit splitting schemes have been shown to give severe stability problems for realistic models of cardiac electro-mechanical coupling. The stability may be improved by adopting semi-implicit schemes, but these give rise to challenges in updating and linearising the active tension. In this paper we present an operator splitting framework for strongly coupled electro-mechanical simulations and discuss alternative strategies for updating and linearising the active stress component. Numerical experiments demonstrate considerable performance increases from an update method based on a generalised Rush-Larsen scheme and a consistent linearisation of active stress based on the first elasticity tensor.

High-coherence picosecond electron bunches from cold atoms.

Ultrafast electron diffraction enables the study of molecular structural dynamics with atomic resolution at subpicosecond timescales, with applications in solid-state physics and rational drug design. Progress with ultrafast electron diffraction has been constrained by the limited transverse coherence of high-current electron sources. Photoionization of laser-cooled atoms can produce electrons of intrinsically high coherence, but has been too slow for ultrafast electron diffraction. Ionization with femtosecond lasers should in principle reduce the electron pulse duration, but the high bandwidth inherent to short laser pulses is expected to destroy the transverse coherence. Here we demonstrate that a two-colour process with femtosecond excitation followed by nanosecond photoionization can produce picosecond electron bunches with high transverse coherence. Ultimately, the unique combination of ultrafast ionization, high coherence and three-dimensional bunch shaping capabilities of cold atom electron sources have the potential for realising the brightness and coherence requirements for single-shot electron diffraction from crystalline biological samples.

Quantitative adjustment for macroprolactin is an integral part of laboratory assessment of hyperprolactinaemia.

INTRODUCTION: Prolactin circulates predominantly as a 23-kDa monomer, and a high-molecular-weight form largely consisting of a complex of prolactin and an anti-prolactin IgG autoantibody, called macroprolactin. This cross-reacts with conventional laboratory assays for prolactin. We here describe how quantitative adjustment for this may assist patient management.In a consecutive series of 218 patients with prolactin elevated to 400 mu/L or more in men (normal range ≤ 180) (n=79, 36.2% of sample) and 1 000 mu/L or more in women (normal range ≤ 500) (n=139, 63.8%) a macroprolactin screen was performed using PEG precipitation. RESULTS: Where present, median macroprolactin as a proportion of total prolactin was in women 13% (percentile 25-percentile 75: 7-25%) and in men 15% (7-30%).The distribution of macroprolactin as a proportion of total prolactin was markedly skewed to the left with 69.7% of women and 62.9% of men having macroprolactin proportion of 20% or less. There was no relation between %macroprolactin and total measured prolactin, age or gender.Of relevance to clinical management, in 24% of men and 20.5% of women, correction for estimated macroprolactin gave an adjusted monomeric prolactin level below the agreed threshold for further investigation, potentially avoiding unnecessarily referral.In our clinical series, quotation of an adjusted monomeric prolactin would have resulted in unnecessary further investigation being avoided in a number of cases. DISCUSSION: Screening for macroprolactin is a key element of laboratory assessment for hyperprolactinaemia.In cases where measured total prolactin is significantly raised, quantitative reporting of estimated monomeric prolactin instead of just 'macroprolactin' positive' can avoid unnecessary investigations.

A nonlinear model of passive muscle viscosity.

The material properties of passive skeletal muscle are critical to proper function and are frequently a target for therapeutic and interventional strategies. Investigations into the passive viscoelasticity of muscle have primarily focused on characterizing the elastic behavior, largely neglecting the viscous component. However, viscosity is a sizeable contributor to muscle stress and extensibility during passive stretch and thus there is a need for characterization of the viscous as well as the elastic components of muscle viscoelasticity. Single mouse muscle fibers were subjected to incremental stress relaxation tests to characterize the dependence of passive muscle stress on time, strain and strain rate. A model was then developed to describe fiber viscoelasticity incorporating the observed nonlinearities. The results of this model were compared with two commonly used linear viscoelastic models in their ability to represent fiber stress relaxation and strain rate sensitivity. The viscous component of mouse muscle fiber stress was not linear as is typically assumed, but rather a more complex function of time, strain and strain rate. The model developed here, which incorporates these nonlinearities, was better able to represent the stress relaxation behavior of fibers under the conditions tested than commonly used models with linear viscosity. It presents a new tool to investigate the changes in muscle viscous stresses with age, injury and disuse.

Minimum Information about a Cardiac Electrophysiology Experiment (MICEE): standardised reporting for model reproducibility, interoperability, and data sharing.

Cardiac experimental electrophysiology is in need of a well-defined Minimum Information Standard for recording, annotating, and reporting experimental data. As a step towards establishing this, we present a draft standard, called Minimum Information about a Cardiac Electrophysiology Experiment (MICEE). The ultimate goal is to develop a useful tool for cardiac electrophysiologists which facilitates and improves dissemination of the minimum information necessary for reproduction of cardiac electrophysiology research, allowing for easier comparison and utilisation of findings by others. It is hoped that this will enhance the integration of individual results into experimental, computational, and conceptual models. In its present form, this draft is intended for assessment and development by the research community. We invite the reader to join this effort, and, if deemed productive, implement the Minimum Information about a Cardiac Electrophysiology Experiment standard in their own work.

Non-iterative imaging of inhomogeneous cold atom clouds using phase retrieval from a single diffraction measurement.

We demonstrate a new imaging technique for cold atom clouds based on phase retrieval from a single diffraction measurement. Most single-shot diffractive imaging methods for cold atoms assume a monomorphic object to extract the column density. The method described here allows quantitative imaging of an inhomogeneous cloud, enabling recovery of either the atomic density or the refractive index, provided the other is known. Using ideas borrowed from density functional theory, we calculate the approximate paraxial diffracted intensity derivative from the measured diffracted intensity distribution and use it to solve the Transport of Intensity Equation (TIE) for the phase of the wave at the detector plane. Back-propagation to the object plane yields the object exit surface wave and then provides a quantitative measurement of either the atomic column density or refractive index. Images of homogeneous clouds showed good quantitative agreement with conventional techniques. An inhomogeneous cloud was created using a cascade electromagnetically induced transparency scheme and images of both phase and amplitude parts of refractive index across the cloud were separately retrieved, showing good agreement with theoretical results.

Generation of a preliminary bovine gene atlas, using expression clustering to annotate gene function.

Genes whose products function in a common biological process are often co-regulated. When regulation occurs at the transcriptional level, co-expressed genes can be detected globally by expression arrays or by sequencing non-normalized cDNA libraries. We examined bovine gene expression in 27 tissues using non-normalized cDNA library sequencing. Contigs were generated from expressed sequence tags whose sequences overlapped. Contigs containing a minimum of five expressed sequence tags were ordered via a hierarchical clustering process, where the distance between the contigs represents their expression pattern similarity across tissues. Gene ontology terms associated with the genes in each cluster showed that co-clustered genes encoded proteins involved in a common biological process. This process can be used to annotate genes of unknown function in the cluster. Gene expression was compared between bovine and human tissues; there were significant correlations between species for each tissue, with the exception of thyroid and placenta. Tissues were also clustered based on the genes they express; tissues with similar physiological functions clustered closely. Based on this information, we generated the first preliminary gene atlas of the bovine genome. Genes with similar expression patterns were clustered, and genes with a common function co-clustered. This method can be used to annotate genes of unknown function in the bovine genome.

The social context of parenting 3-year-old children with developmental delay in the UK.

BACKGROUND: Children with intellectual or developmental disability have significantly poorer health and mental health than their non-disabled peers and are at high risk of social exclusion. The aim of the present paper is to provide information on the circumstances in which 3-year-old children at risk of intellectual or developmental disability are growing up in the UK. METHODS: Secondary analysis of data on 12 689 families in English-speaking monolingual households from the first two waves of the UK's Millennium Cohort Study. A total of 440 children (3% of the weighted sample) were identified as being developmentally delayed. RESULTS: When compared with other children, children with developmental delays were more disadvantaged on every indicator of social and economic disadvantage examined. Two out of three children with developmental delays had been exposed to repeated disadvantage as measured by income poverty, material hardship, social housing and receipt of means-tested benefits. The effect of repeated disadvantage on the risk of developmental delay remained after account was taken of parental education and occupational status. CONCLUSIONS: Young children with delayed development in the UK are likely to be exposed to repeated socio-economic disadvantage. Implications for policy and understanding the nature of the link between poverty and child disability are discussed.

The constituents of Microctonus sp. parasitoid venoms.

Purified RNA transcripts from venom glands dissected from the parasitoid wasp Microctonus hyperodae were copied, cloned and sequenced using traditional dideoxy sequencing methods. Using mass spectrometry analysis of the trypsinised PAGE gel protein bands we identified the RNA transcripts for the 3 most abundant proteins found in the venom and hence obtained their full protein sequence. Other abundant transcripts were also further sequenced. To reduce the effort required to obtain transcript information we dissected venom glands from a second parasitoid, Microctonus aethiopoides (Morocco biotype). The RNA transcripts were purified and reverse transcribed but instead of cloning the cDNA it was directly sequenced using Roche GS20 pyrosequencing. Results from a single GS20 sequencing run provided data similar to that obtained by the traditional methods used in analysing transcripts from M. hyperodae in a fraction of the time and cost. Comparing the transcripts between the two species showed that a similar range of genes are expressed with the putative orthologs of seven of the eight full length genes characterised from M. hyperodae being found in M. aethiopoides. Pyrosequencing should provide a valuable new method for rapidly sampling transcripts from a wide range of specialised insect tissues.

Single nucleotide polymorphisms in human Paneth cell defensin A5 may confer susceptibility to inflammatory bowel disease in a New Zealand Caucasian population.

BACKGROUND: Human Paneth cell alpha-defensins, especially DEFA5, are involved in maintaining homeostasis of the human microbial microflora. Since breakdown of normal mucosal antibacterial defence occurs in inflammatory bowel disease (IBD), variants in the DEFA5 gene could be associated with IBD risk. SUBJECTS: A cohort of 25 patients with indeterminate colitis (IC), 405 with ulcerative colitis (UC), and 385 with Crohn's disease (CD), were compared with 201 control individuals from the Canterbury region in New Zealand. METHODS: A 15 kb haplotype block surrounding DEFA5 contained 35 HapMap markers which were polymorphic in Caucasians. Four markers (A-D) were selected to tag 27 of the 35 markers at r(2)>0.68, and were genotyped in DNA samples. RESULTS: Minor allele frequencies for all single nucleotide polymorphisms (SNPs) were somewhat elevated in patients. Subgroup analysis showed SNP A had odds ratio 1.44 in UC patients with pancolitis (95% C.I. 1.07-1.94), SNP B odds ratio 2.37 in CD patients with onset prior to 17 years age (95% C.I. 1.12-5.03), SNP C odds ratio 1.68 in UC patients with left colonic localisation (95% C.I. 1.12-2.52), and SNP D had odds ratio 1.56 in CD patients with one or more relatives with IBD (95% C.I. 1.03-2.35). Two two-marker haplotypes and one three-marker haplotype were associated with UC (p-values 0.025-0.05). CONCLUSIONS: The SNPs genotyped in our study were surrogates for common variants, and observed associations between these and IBD status are likely due to linkage disequilibrium with a functional common DEFA5 variant. Identifying such functional variants will be prioritized in subsequent work.