Anomalous ion diffusion within skeletal muscle transverse tubule networks

<p>Abstract</p> <p>Background</p> <p>Skeletal muscle fibres contain transverse tubular (t-tubule) networks that allow electrical signals to rapidly propagate into the fibre. These electrical signals are generated by the transport of ions across the t-tubule membranes and this can result in significant changes in ion concentrations within the t-tubules during muscle excitation. During periods of repeated high-frequency activation of skeletal muscle the t-tubule K⁺concentration is believed to increase significantly and diffusive K⁺transport from the t-tubules into the interstitial space provides a mechanism for alleviating muscle membrane depolarization. However, the tortuous nature of the highly branched space-filling t-tubule network impedes the diffusion of material through the network. The effective diffusion coefficient for ions in the t-tubules has been measured to be approximately five times lower than in free solution, which is significantly different from existing theoretical values of the effective diffusion coefficient that range from 2–3 times lower than in free solution. To resolve this discrepancy, in this paper we study the process of diffusion within electron microscope scanned sections of the skeletal muscle t-tubule network using mathematical modelling and computer simulation techniques. Our model includes t-tubule geometry, tautness, hydrodynamic and non-planar network factors.</p> <p>Results</p> <p>Using our model we found that the t-tubule network geometry reduced the K⁺diffusion coefficient to 19–27% of its value in free solution, which is consistent with the experimentally observed value of 21% and is significantly smaller than existing theoretical values that range from 32–50%. We also found that diffusion in the t-tubules is anomalous for skeletal muscle fibres with a diameter of less than approximately 10–20 μm as a result of obstructed diffusion. We also observed that the [K⁺] within the interior of the t-tubule network during high-frequency activation is greater for fibres with a larger diameter. Smaller skeletal muscle fibres are therefore more resistant to membrane depolarization. Because the t-tubule network is anisotropic and inhomogeneous, we also found that the [K⁺] distribution generated within the network was irregular for fibres of small diameter.</p> <p>Conclusion</p> <p>Our model explains the measured effective diffusion coefficient for ions in skeletal muscle t-tubules.</p

Sensory Symptom Profiles and Co-Morbidities in Painful Radiculopathy

Painful radiculopathies (RAD) and classical neuropathic pain syndromes (painful diabetic polyneuropathy, postherpetic neuralgia) show differences how the patients express their sensory perceptions. Furthermore, several clinical trials with neuropathic pain medications failed in painful radiculopathy. Epidemiological and clinical data of 2094 patients with painful radiculopathy were collected within a cross sectional survey (painDETECT) to describe demographic data and co-morbidities and to detect characteristic sensory abnormalities in patients with RAD and compare them with other neuropathic pain syndromes. Common co-morbidities in neuropathic pain (depression, sleep disturbance, anxiety) do not differ considerably between the three conditions. Compared to other neuropathic pain syndromes touch-evoked allodynia and thermal hyperalgesia are relatively uncommon in RAD. One distinct sensory symptom pattern (sensory profile), i.e., severe painful attacks and pressure induced pain in combination with mild spontaneous pain, mild mechanical allodynia and thermal hyperalgesia, was found to be characteristic for RAD. Despite similarities in sensory symptoms there are two important differences between RAD and other neuropathic pain disorders: (1) The paucity of mechanical allodynia and thermal hyperalgesia might be explained by the fact that the site of the nerve lesion in RAD is often located proximal to the dorsal root ganglion. (2) The distinct sensory profile found in RAD might be explained by compression-induced ectopic discharges from a dorsal root and not necessarily by nerve damage. These differences in pathogenesis might explain why medications effective in DPN and PHN failed to demonstrate efficacy in RAD

Validation of an Estonian version of the Parkinson's Disease Questionnaire (PDQ-39)

<p>Abstract</p> <p>Introduction</p> <p>Diagnosis and management of Parkinson's disease (PD) rely heavily on evaluation of clinical symptoms and patients' subjective perception of their condition. The purpose of this study was to evaluate the validity, acceptability, and reliability of the Estonian version of the 39-question Parkinson 's disease Questionnaire (PDQ-39).</p> <p>Methods</p> <p>Study subjects were approached during their regular clinic follow-up visits. 104 patients consented to the study and 81 completed questionnaires were used for subsequent testing of psychometric characteristics, validity and reliability.</p> <p>Results</p> <p>The content validity was assessed through qualitative content analysis during the pilot study. The patients indicated that the questions were relevant to measure the quality of life of people with PD.</p> <p>The analysis of means showed that the ceiling and floor effects of domain results were within the limits of 15% of Summary Index and of all domains except Stigma, Social Support and Communication where the ceiling effect was 16% to 24% of the responses. Convergent validity was interpreted through correlation between disease severity and PDQ-39 domains. There was a statistically significant difference between the domain scores in patients with mild versus moderate PD in domains of Mobility, ADL, and Communication but not for Stigma, Social Support and Cognition. The reliability was good, Cronbach alpha for all domains and summary index was over 0.8 and item-test correlations between domains and summary index ranged from 0.56 to 0.83.</p> <p>Conclusion</p> <p>The psychometric characteristics of an Estonian version of the PDQ-39 were satisfactory. The results of this study were comparable to the results of previous validation studies in other cultural settings in UK, USA, Canada, Spain and Italy.</p> <p>The Estonian version of the PDQ-39 is an acceptable, valid and reliable instrument for quality of life measurement in PD patients.</p

Meta-analysis of genome-wide linkage studies of asthma and related traits

<p>Abstract</p> <p>Background</p> <p>Asthma and allergy are complex multifactorial disorders, with both genetic and environmental components determining disease expression. The use of molecular genetics holds great promise for the identification of novel drug targets for the treatment of asthma and allergy. Genome-wide linkage studies have identified a number of potential disease susceptibility loci but replication remains inconsistent. The aim of the current study was to complete a meta-analysis of data from genome-wide linkage studies of asthma and related phenotypes and provide inferences about the consistency of results and to identify novel regions for future gene discovery.</p> <p>Methods</p> <p>The rank based genome-scan meta-analysis (GSMA) method was used to combine linkage data for asthma and related traits; bronchial hyper-responsiveness (BHR), allergen positive skin prick test (SPT) and total serum Immunoglobulin E (IgE) from nine Caucasian asthma populations.</p> <p>Results</p> <p>Significant evidence for susceptibility loci was identified for quantitative traits including; BHR (989 pedigrees, n = 4,294) 2p12-q22.1, 6p22.3-p21.1 and 11q24.1-qter, allergen SPT (1,093 pedigrees, n = 4,746) 3p22.1-q22.1, 17p12-q24.3 and total IgE (729 pedigrees, n = 3,224) 5q11.2-q14.3 and 6pter-p22.3. Analysis of the asthma phenotype (1,267 pedigrees, n = 5,832) did not identify any region showing genome-wide significance.</p> <p>Conclusion</p> <p>This study represents the first linkage meta-analysis to determine the relative contribution of chromosomal regions to the risk of developing asthma and atopy. Several significant results were obtained for quantitative traits but not for asthma confirming the increased phenotype and genetic heterogeneity in asthma. These analyses support the contribution of regions that contain previously identified asthma susceptibility genes and provide the first evidence for susceptibility loci on 5q11.2-q14.3 and 11q24.1-qter.</p

Image Texture Characterization Using the Discrete Orthonormal S-Transform

We present a new efficient approach for characterizing image texture based on a recently published discrete, orthonormal space-frequency transform known as the DOST. We develop a frequency-domain implementation of the DOST in two dimensions for the case of dyadic frequency sampling. Then, we describe a rapid and efficient approach to obtain local spatial frequency information for an image and show that this information can be used to characterize the horizontal and vertical frequency patterns in synthetic images. Finally, we demonstrate that DOST components can be combined to obtain a rotationally invariant set of texture features that can accurately classify a series of texture patterns. The DOST provides the computational efficiency and multi-scale information of wavelet transforms, while providing texture features in terms of Fourier frequencies. It outperforms leading wavelet-based texture analysis methods

L1TD1 Is a Marker for Undifferentiated Human Embryonic Stem Cells

Human embryonic stem cells (hESC) are stem cells capable of differentiating into cells representative of the three primary embryonic germ layers. There has been considerable interest in understanding the mechanisms regulating stem cell pluripotency, which will ultimately lead to development of more efficient methods to derive and culture hESC. In particular, Oct4, Sox2 and Nanog are transcription factors known to be important in maintenance of hESC. However, many of the downstream targets of these transcription factors are not well characterized. Furthermore, it remains unknown whether additional novel stem cell factors are involved in the establishment and maintenance of the stem cell state.Here we show that a novel gene, L1TD1 (also known as FLJ10884 or ECAT11), is abundantly expressed in undifferentiated hESC. Differentiation of hESC via embryoid body (EB) formation or BMP4 treatment results in the rapid down-regulation of L1TD1 expression. Furthermore, populations of undifferentiated and differentiated hESC were sorted using the stem cell markers SSEA4 and TRA160. Our results show that L1TD1 is enriched in the SSEA4-positive or TRA160-positive population of hESC. Using chromatin immunoprecipitation we found enriched association of Nanog to the predicted promoter region of L1TD1. Furthermore, siRNA-mediated knockdown of Nanog in hESC also resulted in downregulation of L1TD1 expression. Finally, using luciferase reporter assay we demonstrated that Nanog can activate the L1TD1 upstream promoter region. Altogether, these results provide evidence that L1TD1 is a downstream target of Nanog.Taken together, our results suggest that L1TD1 is a downstream target of Nanog and represents a useful marker for identifying undifferentiated hESC