Patients with chronic neck pain demonstrate altered patterns of muscle activation during performance of a functional upper limb task

Study Design. Cross-sectional study. Objective. This study compared neck muscle activation patterns during and after a repetitive upper limb task between patients with idiopathic neck pain, whiplash-associated disorders, and controls. Summary of Background Data. Previous studies have identified altered motor control of the upper trapezius during functional tasks in patients with neck pain. Whether the cervical flexor muscles demonstrate altered motor control during functional activities is unknown. Methods. Electromyographic activity was recorded from the sternocleidomastoid, anterior scalenes, and upper trapezius muscles. Root mean square electromyographic amplitude was calculated during and on completion of a functional task. Results. A general trend was evident to suggest greatest electromyograph amplitude in the sternocleidomastoid, anterior scalenes, and left upper trapezius muscles for the whiplash-associated disorders group, followed by the idiopathic group, with lowest electromyographic amplitude recorded for the control group. A reverse effect was apparent for the right upper trapezius muscle. The level of perceived disability ( Neck Disability Index score) had a significant effect on the electromyographic amplitude recorded between neck pain patients. Conclusions. Patients with neck pain demonstrated greater activation of accessory neck muscles during a repetitive upper limb task compared to asymptomatic controls. Greater activation of the cervical muscles in patients with neck pain may represent an altered pattern of motor control to compensate for reduced activation of painful muscles. Greater perceived disability among patients with neck pain accounted for the greater electromyographic amplitude of the superficial cervical muscles during performance of the functional task.

Functional serotonin 5-HT4 receptors in porcine and human ventricular myocardium with increased 5-HT4 mRNA in heart failure

Serotonin (5-hydroxytryptamine, 5-HT) increases contractile force and elicits arrhythmias through 5-HT4 receptors in porcine and human atrium, but its ventricular effects are unknown. We now report functional 5-HT4 receptors in porcine and human ventricle. 5-HT4 mRNA levels were determined in porcine and human ventricles and contractility studied in ventricular trabeculae. Cyclic AMP-dependent protein kinase (PKA) activity was measured in porcine ventricle. Porcine and human ventricles expressed 5-HT4 receptor mRNA. Ventricular 5-HT4(b) mRNA was increased by four times in 20 failing human hearts compared with five donor hearts. 5-HT increased contractile force maximally by 16% (EC50=890 nM) and PKA activity by 20% of the effects of (-)-isoproterenol (200 muM) in ventricular trabeculae from new-born piglets in the presence of the phosphodiesterase-inhibitor 3-isobutyl-1-methylxanthine. In ventricular trabeculae from adult pigs (3-isobutyl-1-methylxanthine present) 5-HT increased force by 32% (EC50=60 nM) and PKA activity by 39% of (-)-iso-proterenol. In right and left ventricular trabeculae from failing hearts, exposed to modified Krebs solution, 5-HT produced variable increases in contractile force in right ventricular trabeculae from 4 out of 6 hearts and in left ventricular trabeculae from 3 out of 3 hearts- range 1-39% of (-)-isoproterenol, average 8%. In 11 left ventricular trabeculae from the failing hearts of four beta-blocker-treated patients, pre-exposed to a relaxant solution with 0.5 mM Ca2+ and 1.2 mM Mg2+ followed by a switch to 2.5 mM Ca2+ and 1 mM Mg2+, 5-HT (1-100 muM, 3-isobutyl-1-melhylxanthine present) consistently increased contractile force and hastened relaxation by 46% and 25% of (-)-isoproterenol respectively. 5-HT caused arrhythmias in three trabeculae from 3 out of I I patients. In the absence of phosphodiesterase inhibitor, 5-HT increased force in two trabeculae, but not in another six trabeculae from 4 patients. All 5-HT responses were blocked by 5-HT4 receptor antagonists. We conclude that phosphodiesterase inhibition uncovers functional ventricular 5-HT4 receptors, coupled to a PKA pathway, through which 5-HT enhances contractility, hastens relaxation and can potentially cause arrhythmias.

Pyramidal neurons of granular prefrontal cortex of the galago: Complexity in evolution of the psychic cell in primates

Typically, cognitive abilities of humans have been attributed to their greatly expanded cortical mantle, granular prefrontal cortex (gPFC) in particular. Recently we have demonstrated systematic differences in microstructure of gPFC in different species. Specifically, pyramidal cells in adult human gPFC are considerably more spinous than those in the gPFC of the macaque monkey, which are more spinous than those in the gPFC of marmoset and owl monkeys. As most cortical dendritic spines receive at least one excitatory input, pyramidal cells in these different species putatively receive different numbers of inputs. These differences in the gPFC pyramidal cell phenotype may be of fundamental importance in determining the functional characteristics of prefrontal circuitry and hence the cognitive styles of the different species. However, it remains unknown as to why the gPFC pyramidal cell phenotype differs between species. Differences could be attributed to, among other things, brain size, relative size of gPFC, or the lineage to which the species belong. Here we investigated pyramidal cells in the dorsolateral gPFC of the prosimian galago to extend the basis for comparison. We found these cells to be less spinous than those in human, macaque, and marmoset. (c) 2005 Wiley-Liss, Inc.

A scatterometer neural network sensor model with input noise

The ERS-1 satellite carries a scatterometer which measures the amount of radiation scattered back toward the satellite by the ocean's surface. These measurements can be used to infer wind vectors. The implementation of a neural network based forward model which maps wind vectors to radar backscatter is addressed. Input noise cannot be neglected. To account for this noise, a Bayesian framework is adopted. However, Markov Chain Monte Carlo sampling is too computationally expensive. Instead, gradient information is used with a non-linear optimisation algorithm to find the maximum em a posteriori probability values of the unknown variables. The resulting models are shown to compare well with the current operational model when visualised in the target space.

A scatterometer neural network sensor model with input noise

The ERS-1 satellite carries a scatterometer which measures the amount of radiation scattered back toward the satellite by the ocean's surface. These measurements can be used to infer wind vectors. The implementation of a neural network based forward model which maps wind vectors to radar backscatter is addressed. Input noise cannot be neglected. To account for this noise, a Bayesian framework is adopted. However, Markov Chain Monte Carlo sampling is too computationally expensive. Instead, gradient information is used with a non-linear optimisation algorithm to find the maximum em a posteriori probability values of the unknown variables. The resulting models are shown to compare well with the current operational model when visualised in the target space.

Functional characterization of GABAergic pallidopallidal and striatopallidal synapses in the rat globus pallidus in vitro

As a central integrator of basal ganglia function, the external segment of the globus pallidus (GP) plays a critical role in the control of voluntary movement. Driven by intrinsic mechanisms and excitatory glutamatergic inputs from the subthalamic nucleus, GP neurons receive GABAergic inhibitory input from the striatum (Str-GP) and from local collaterals of neighbouring pallidal neurons (GP-GP). Here we provide electrophysiological evidence for functional differences between these two inhibitory inputs. The basic synaptic characteristics of GP-GP and Str-GP GABAergic synapses were studied using whole-cell recordings with paired-pulse and train stimulation protocols and variance-mean (VM) analysis. We found (i) IPSC kinetics are consistent with local collaterals innervating the soma and proximal dendrites of GP neurons whereas striatal inputs innervate more distal regions. (ii) Compared to GP-GP synapses Str-GP synapses have a greater paired-pulse ratio, indicative of a lower probability of release. This was confirmed using VM analysis. (iii) In response to 20 and 50 Hz train stimulation, GP-GP synapses are weakly facilitatory in 1 mm external calcium and depressant in 2.4 mm calcium. This is in contrast to Str-GP synapses which display facilitation under both conditions. This is the first quantitative study comparing the properties of GP-GP and Str-GP synapses. The results are consistent with the differential location of these inhibitory synapses and subtle differences in their release probability which underpin stable GP-GP responses and robust short-term facilitation of Str-GP responses. These fundamental differences may provide the physiological basis for functional specialization.

Identifying a novel functional domain within the p115 tethering factor required for Golgi ribbon assembly and membrane trafficking

The tethering factor p115 has been shown to facilitate Golgi biogenesis and membrane traffic in cells in culture. However, the role of p115 within an intact animal is largely unknown. Here, we document that RNAi-mediated depletion of p115 in C. elegans causes accumulation of the yolk protein (YP170) in body cavity and the retention of the yolk receptor RME-2 in the ER and the Golgi within oocytes.Structure-function analyses of p115 have identified two homology (H1-2) regions within the N-terminal globular head and the coiled-coil 1 (CC1) domain as essential for p115 function. We identify a novel C-terminal domain of p115 as necessary for Golgi ribbon formation and cargo trafficking. We show that p115 mutants lacking the fourth CC domain (CC4) act in a dominant negative manner to disrupt Golgi and prevent cargo trafficking in cells containing endogenous p115. Furthermore, using RNAi-mediated "replacement" strategy we show that CC4 is necessary for Golgi ribbon formation and membrane trafficking in cells depleted of endogenous p115.p115 has been shown to bind a subset of ER-Golgi SNAREs through CC1 and CC4 domains (Shorter et al., 2002). Our findings show that CC4 is required for p115 function and suggest that both the CC1 and the CC4 SNARE-binding motifs may participate in p115-mediated membrane tethering.

The impact of general intellectual ability and white matter volume on the functional outcome of patients with bipolar disorder and their relatives

Background: There is substantial evidence that cognitive deficits and brain structural abnormalities are present in patients with Bipolar Disorder (BD) and in their first-degree relatives. Previous studies have demonstrated associations between cognition and functional outcome in BD patients but have not examined the role of brain morphological changes. Similarly, the functional impact of either cognition or brain morphology in relatives remains unknown. Therefore we focused on delineating the relationship between psychosocial functioning, cognition and brain structure, in relation to disease expression and genetic risk for BD. Methods: Clinical, cognitive and brain structural measures were obtained from 41 euthymic BD patients and 50 of their unaffected first-degree relatives. Psychosocial function was evaluated using the General Assessment of Functioning (GAF) scale. We examined the relationship between level of functioning and general intellectual ability (IQ), memory, attention, executive functioning, symptomatology, illness course and total gray matter, white matter and cerebrospinal fluid volumes. Limitations: Cross-sectional design. Results: Multiple regression analyses revealed that IQ, total white matter volume and a predominantly depressive illness course were independently associated with functional outcome in BD patients, but not in their relatives, and accounted for a substantial proportion (53%) of the variance in patients' GAF scores. There were no significant domain-specific associations between cognition and outcome after consideration of IQ. Conclusions: Our results emphasise the role of IQ and white matter integrity in relation to outcome in BD and carry significant implications for treatment interventions. © 2010 Elsevier B.V.

Fully probabilistic control for stochastic nonlinear control systems with input dependent noise

Robust controllers for nonlinear stochastic systems with functional uncertainties can be consistently designed using probabilistic control methods. In this paper a generalised probabilistic controller design for the minimisation of the Kullback-Leibler divergence between the actual joint probability density function (pdf) of the closed loop control system, and an ideal joint pdf is presented emphasising how the uncertainty can be systematically incorporated in the absence of reliable systems models. To achieve this objective all probabilistic models of the system are estimated from process data using mixture density networks (MDNs) where all the parameters of the estimated pdfs are taken to be state and control input dependent. Based on this dependency of the density parameters on the input values, explicit formulations to the construction of optimal generalised probabilistic controllers are obtained through the techniques of dynamic programming and adaptive critic methods. Using the proposed generalised probabilistic controller, the conditional joint pdfs can be made to follow the ideal ones. A simulation example is used to demonstrate the implementation of the algorithm and encouraging results are obtained.

Constrained nonparametric estimation of input distance function

This paper proposes a constrained nonparametric method of estimating an input distance function. A regression function is estimated via kernel methods without functional form assumptions. To guarantee that the estimated input distance function satisfies its properties, monotonicity constraints are imposed on the regression surface via the constraint weighted bootstrapping method borrowed from statistics literature. The first, second, and cross partial analytical derivatives of the estimated input distance function are derived, and thus the elasticities measuring input substitutability can be computed from them. The method is then applied to a cross-section of 3,249 Norwegian timber producers.

Generalizing of Neural Nets: Functional Nets of Special Type

Special generalizing for the artificial neural nets: so called RFT – FN – is under discussion in the report. Such refinement touch upon the constituent elements for the conception of artificial neural network, namely, the choice of main primary functional elements in the net, the way to connect them(topology) and the structure of the net as a whole. As to the last, the structure of the functional net proposed is determined dynamically just in the constructing the net by itself by the special recurrent procedure. The number of newly joining primary functional elements, the topology of its connecting and tuning of the primary elements is the content of the each recurrent step. The procedure is terminated under fulfilling “natural” criteria relating residuals for example. The functional proposed can be used in solving the approximation problem for the functions, represented by its observations, for classifying and clustering, pattern recognition, etc. Recurrent procedure provide for the versatile optimizing possibilities: as on the each step of the procedure and wholly: by the choice of the newly joining elements, topology, by the affine transformations if input and intermediate coordinate as well as by its nonlinear coordinate wise transformations. All considerations are essentially based, constructively and evidently represented by the means of the Generalized Inverse.

Optimum Trajectory of Dynamic Input-Output Balance Model for Open Economy

When export and import is connected with output of basic production, and criterion functional represents a final state of economy, the generalization of classical qualitative results of the main-line theory on a case of dynamic input-output balance optimization model for open economy is given.

The functional neuroanatomy of auditory sensory gating and its behavioural implications

Auditory sensory gating (ASG) is the ability in individuals to suppress incoming irrelevant sensory input, indexed by evoked response to paired auditory stimuli. ASG is impaired in psychopathology such as schizophrenia, in which it has been proposed as putative endophenotype. This study aims to characterise electrophysiological properties of the phenomenon using MEG in time and frequency domains as well as to localise putative networks involved in the process at both sensor and source level. We also investigated the relationship between ASG measures and personality profiles in healthy participants in the light of its candidate endophenotype role in psychiatric disorders. Auditory evoked magnetic fields were recorded in twenty seven healthy participants by P50 ‘paired-click’ paradigm presented in pairs (conditioning stimulus S1- testing stimulus S2) at 80dB, separated by 250msec with inter trial interval of 7-10 seconds. Gating ratio in healthy adults ranged from 0.5 to 0.8 suggesting dimensional nature of P50 ASG. The brain regions active during this process were bilateral superior temporal gyrus (STG) and bilateral inferior frontal gyrus (IFG); activation was significantly stronger in IFG during S2 as compared to S1 (at p<0.05). Measures of effective connectivity between these regions using DCM modelling revealed the role of frontal cortex in modulating ASG as suggested by intracranial studies, indicating major role of inhibitory interneuron connections. Findings from this study identified a unique event-related oscillatory pattern for P50 ASG with alpha (STG)-beta (IFG) desynchronization and increase in cortical oscillatory gamma power (IFG) during S2 condition as compared to S1. These findings show that the main generator for P50 response is within temporal lobe and that inhibitory interneurons and gamma oscillations in the frontal cortex contributes substantially towards sensory gating. Our findings also show that ASG is a predictor of personality profiles (introvert vs extrovert dimension).

Dissecting the Functional Impacts of Non-Coding Genetic Variation

A large proportion of the variation in traits between individuals can be attributed to variation in the nucleotide sequence of the genome. The most commonly studied traits in human genetics are related to disease and disease susceptibility. Although scientists have identified genetic causes for over 4,000 monogenic diseases, the underlying mechanisms of many highly prevalent multifactorial inheritance disorders such as diabetes, obesity, and cardiovascular disease remain largely unknown. Identifying genetic mechanisms for complex traits has been challenging because most of the variants are located outside of protein-coding regions, and determining the effects of such non-coding variants remains difficult. In this dissertation, I evaluate the hypothesis that such non-coding variants contribute to human traits and diseases by altering the regulation of genes rather than the sequence of those genes. I will specifically focus on studies to determine the functional impacts of genetic variation associated with two related complex traits: gestational hyperglycemia and fetal adiposity. At the genomic locus associated with maternal hyperglycemia, we found that genetic variation in regulatory elements altered the expression of the HKDC1 gene. Furthermore, we demonstrated that HKDC1 phosphorylates glucose in vitro and in vivo, thus demonstrating that HKDC1 is a fifth human hexokinase gene. At the fetal-adiposity associated locus, we identified variants that likely alter VEPH1 expression in preadipocytes during differentiation. To make such studies of regulatory variation high-throughput and routine, we developed POP-STARR, a novel high throughput reporter assay that can empirically measure the effects of regulatory variants directly from patient DNA. By combining targeted genome capture technologies with STARR-seq, we assayed thousands of haplotypes from 760 individuals in a single experiment. We subsequently used POP-STARR to identify three key features of regulatory variants: that regulatory variants typically have weak effects on gene expression; that the effects of regulatory variants are often coordinated with respect to disease-risk, suggesting a general mechanism by which the weak effects can together have phenotypic impact; and that nucleotide transversions have larger impacts on enhancer activity than transitions. Together, the findings presented here demonstrate successful strategies for determining the regulatory mechanisms underlying genetic associations with human traits and diseases, and value of doing so for driving novel biological discovery.

First Triassic tetrapod (Sauropterygia, Nothosauridae) from Castilla y León: evidence of an unknown taxon for the Spanish record

Several vertebrae of a sauropterygian specimen have been recovered in Fuencaliente de Medinaceli (Soria Province, Castilla y León, Spain). The remains come from Middle–Upper Triassic Muschelkalk Facies. This finding represents the first documented evidence of a Triassic tetrapod in Castilla y León. The vertebrae belong to Nothosaurus, a sauropterygian genus found in Europe, Middle East, North of Africa and China. This genus is poorly-known in the Iberian record. The new remains constitute the first evidence of the species Nothosaurus giganteus, or a related taxon, in the Iberian Peninsula. This study reveals the occurrence of at least two species of the sauropterygian Nothosaurus in the Spanish record.