Scoliosis Research Society members attitudes towards physical therapy and physiotherapeutic scoliosis specific exercises for adolescent idiopathic scoliosis

Background: Attitudes regarding non-operative treatment for adolescent idiopathic scoliosis (AIS) may be changing with the publication of BRAiST. Physiotherapeutic Scoliosis Specific Exercises (PSSE) are used to treat AIS, but high-quality evidence is limited. The purpose of this study is to assess the attitudes of members of the Scoliosis Research Society towards PSSE. Methods: A survey was sent to all SRS members with questions on use of Physical Therapy (PT) and PSSE for AIS. Results: The majority of the 263 respondents were from North America (175, 67 %), followed by Asia (37, 14 %) and Europe (36, 14 %). The majority of respondents (166, 63 %) prescribed neither PT nor PSSE, 28 (11 %) prescribed both PT and PSSE, 39 (15 %) prescribe PT only and 30 (11 %) prescribe PSSE only. PT was prescribed by 67 respondents, as an adjunct to bracing (39) and in small curves (32); with goals to improve aesthetics (27) and post-operative outcomes (25). Of the 196 who do not prescribe PT, the main reasons were lack of evidence (149) and the perception that PT had no value (112). PSSE was prescribed by 58 respondents. The most common indication was as an adjunct to bracing (49) or small curves (41); with goals to improve aesthetics (36), prevent curve progression (35) and improve quality of life (31). Of the respondents who do not prescribe PSSE, the main reasons were lack of supporting research (149), a perception that PSSE had no value (108), and lack of access (63). Most respondents state that evidence of efficacy may increase the role of PSSE, with 85 % (223 of 263) favoring funding PSSE studies by the SRS. Conclusion: The results show that 22 % of the respondents use PSSE for AIS, skepticism remains regarding the benefit of PSSE for AIS. Support for SRS funded research suggests belief that there is potential benefit from PSSE and the best way to assess that potential is through evidence development

Muscle-specific ablation of glucose transporter 1 (GLUT1) does not impair basal or overload-stimulated skeletal muscle glucose uptake

Glucose transporter 1 (GLUT1) is believed to solely mediate basal (insulin-independent) glucose uptake in skeletal muscle; yet recent work has demonstrated that mechanical overload, a model of resistance exercise training, increases muscle GLUT1 levels. The primary objective of this study was to determine if GLUT1 is necessary for basal or overload-stimulated muscle glucose uptake. Muscle-specific GLUT1 knockout (mGLUT1KO) mice were generated and examined for changes in body weight, body composition, metabolism, systemic glucose regulation, muscle glucose transporters, and muscle

ICESTARS : integrated circuit/EM simulation and design technologies for advanced radio systems-on-chip

ICESTARS solved a series of critical issues in the currently available infrastructure for the design and simulation of new and highly-complex Radio Frequency (RF) front ends operating beyond 10 and up to 100 GHz. Future RF designs demand an increasing blend of analog and digital functionalities. The super and extremely high frequency (SHF, 3-30GHz, and EHF, 30-300GHz) ranges will be used to accomplish future demands for higher capacity channels. With todays frequency bands of approximately 1 to 3 GHz it is impossible to realize extremely high data transfer rates. Only a new generation of CAD and EDA tools will ensure the realization of complex nanoscale designs. It necessitates both new modeling approaches and new mathematical solution procedures for differential equations with largely differing time scales, analysis of coupled systems of DAEs (circuit equations) and PDEs (Maxwell equations for electromagnetic couplings) plus numerical simulations with mixed analog and digital signals. In ICESTARS new techniques and mathematical models working in highly integrated environments were developed to resolve this dilemma. The ICESTARS research area covered the three domains of RF design: (1) time-domain techniques, (2) frequency-domain techniques, and (3) EM analysis and coupled EM circuit analysis. The ICESTARS consortium comprised two industrial partners (NXP Semiconductors, Infineon Technologies AG), two SMEs (Magwel, AWR-APLAC) and five universities (Upper Austria, Cologne, Oulu, Wuppertal, Aalto), involving mathematicians, electronic engineers, and software engineers

The Cell Signaling Adaptor Protein EPS-8 Is Essential for C. elegans Epidermal Elongation and Interacts with the Ankyrin Repeat Protein VAB-19

The epidermal cells of the C. elegans embryo undergo coordinated cell shape changes that result in the morphogenetic process of elongation. The cytoskeletal ankyrin repeat protein VAB-19 is required for cell shape changes and localizes to cell-matrix attachment structures. The molecular functions of VAB-19 in this process are obscure, as no previous interactors for VAB-19 have been described.In screens for VAB-19 binding proteins we identified the signaling adaptor EPS-8. Within C. elegans epidermal cells, EPS-8 and VAB-19 colocalize at cell-matrix attachment structures. The central domain of EPS-8 is necessary and sufficient for its interaction with VAB-19. eps-8 null mutants, like vab-19 mutants, are defective in epidermal elongation and in epidermal-muscle attachment. The eps-8 locus encodes two isoforms, EPS-8A and EPS-8B, that appear to act redundantly in epidermal elongation. The function of EPS-8 in epidermal development involves its N-terminal PTB and central domains, and is independent of its C-terminal SH3 and actin-binding domains. VAB-19 appears to act earlier in the biogenesis of attachment structures and may recruit EPS-8 to these structures.EPS-8 and VAB-19 define a novel pathway acting at cell-matrix attachments to regulate epithelial cell shape. This is the first report of a role for EPS-8 proteins in cell-matrix attachments. The existence of EPS-8B-like isoforms in Drosophila suggests this function of EPS-8 proteins could be conserved among other organisms

HIV Protease Inhibitors Act as Competitive Inhibitors of the Cytoplasmic Glucose Binding Site of GLUTs with Differing Affinities for GLUT1 and GLUT4

The clinical use of several first generation HIV protease inhibitors (PIs) is associated with the development of insulin resistance. Indinavir has been shown to act as a potent reversible noncompetitive inhibitor of zero-trans glucose influx via direct interaction with the insulin responsive facilitative glucose transporter GLUT4. Newer drugs within this class have differing effects on insulin sensitivity in treated patients. GLUTs are known to contain two distinct glucose-binding sites that are located on opposite sides of the lipid bilayer. To determine whether interference with the cytoplasmic glucose binding site is responsible for differential effects of PIs on glucose transport, intact intracellular membrane vesicles containing GLUT1 and GLUT4, which have an inverted transporter orientation relative to the plasma membrane, were isolated from 3T3-L1 adipocytes. The binding of biotinylated ATB-BMPA, a membrane impermeable bis-mannose containing photolabel, was determined in the presence of indinavir, ritonavir, atazanavir, tipranavir, and cytochalasin b. Zero-trans 2-deoxyglucose transport was measured in both 3T3-L1 fibroblasts and primary rat adipocytes acutely exposed to these compounds. PI inhibition of glucose transport correlated strongly with the PI inhibition of ATB-BMPA/transporter binding. At therapeutically relevant concentrations, ritonavir was not selective for GLUT4 over GLUT1. Indinavir was found to act as a competitive inhibitor of the cytoplasmic glucose binding site of GLUT4 with a KI of 8.2 µM. These data establish biotinylated ATB-BMPA as an effective probe to quantify accessibility of the endofacial glucose-binding site in GLUTs and reveal that the ability of PIs to block this site differs among drugs within this class. This provides mechanistic insight into the basis for the clinical variation in drug-related metabolic toxicity

A Phosphatidylinositol 3-Kinase/Protein Kinase B-independent Activation of Mammalian Target of Rapamycin Signaling Is Sufficient to Induce Skeletal Muscle Hypertrophy

Overexpression of Rheb activates mTOR signaling via a PI3K/PKB-independent mechanism and is sufficient to induce skeletal muscle hypertrophy. The hypertrophic effects of Rheb are driven through a rapamycin-sensitive (RS) mechanism, mTOR is the RS element that confers the hypertrophy and the kinase activity of mTOR is necessary for this event

An Integrated Strategy to Study Muscle Development and Myofilament Structure in Caenorhabditis elegans

A crucial step in the development of muscle cells in all metazoan animals is the assembly and anchorage of the sarcomere, the essential repeat unit responsible for muscle contraction. In Caenorhabditis elegans, many of the critical proteins involved in this process have been uncovered through mutational screens focusing on uncoordinated movement and embryonic arrest phenotypes. We propose that additional sarcomeric proteins exist for which there is a less severe, or entirely different, mutant phenotype produced in their absence. We have used Serial Analysis of Gene Expression (SAGE) to generate a comprehensive profile of late embryonic muscle gene expression. We generated two replicate long SAGE libraries for sorted embryonic muscle cells, identifying 7,974 protein-coding genes. A refined list of 3,577 genes expressed in muscle cells was compiled from the overlap between our SAGE data and available microarray data. Using the genes in our refined list, we have performed two separate RNA interference (RNAi) screens to identify novel genes that play a role in sarcomere assembly and/or maintenance in either embryonic or adult muscle. To identify muscle defects in embryos, we screened specifically for the Pat embryonic arrest phenotype. To visualize muscle defects in adult animals, we fed dsRNA to worms producing a GFP-tagged myosin protein, thus allowing us to analyze their myofilament organization under gene knockdown conditions using fluorescence microscopy. By eliminating or severely reducing the expression of 3,300 genes using RNAi, we identified 122 genes necessary for proper myofilament organization, 108 of which are genes without a previously characterized role in muscle. Many of the genes affecting sarcomere integrity have human homologs for which little or nothing is known

Regulation of mTORC1 Signaling by pH

BACKGROUND: Acidification of the cytoplasm and the extracellular environment is associated with many physiological and pathological conditions, such as intense exercise, hypoxia and tumourigenesis. Acidification affects important cellular functions including protein synthesis, growth, and proliferation. Many of these vital functions are controlled by mTORC1, a master regulator protein kinase that is activated by various growth-stimulating signals and inactivated by starvation conditions. Whether mTORC1 can also respond to changes in extracellular or cytoplasmic pH and play a role in limiting anabolic processes in acidic conditions is not known. METHODOLOGY/FINDINGS: We examined the effects of acidifying the extracellular medium from pH 7.4 to 6.4 on human breast carcinoma MCF-7 cells and immortalized mouse embryo fibroblasts. Decreasing the extracellular pH caused intracellular acidification and rapid, graded and reversible inhibition of mTORC1, assessed by measuring the phosphorylation of the mTORC1 substrate S6K. Fibroblasts deleted of the tuberous sclerosis complex TSC2 gene, a major negative regulator of mTORC1, were unable to inhibit mTORC1 in acidic extracellular conditions, showing that the TSC1-TSC2 complex is required for this response. Examination of the major upstream pathways converging on the TSC1-TSC2 complex showed that Akt signaling was unaffected by pH but that the Raf/MEK/ERK pathway was inhibited. Inhibition of MEK with drugs caused only modest mTORC1 inhibition, implying that other unidentified pathways also play major roles. CONCLUSIONS: This study reveals a novel role for the TSC1/TSC2 complex and mTORC1 in sensing variations in ambient pH. As a common feature of low tissue perfusion, low glucose availability and high energy expenditure, acidic pH may serve as a signal for mTORC1 to downregulate energy-consuming anabolic processes such as protein synthesis as an adaptive response to metabolically stressful conditions

Health Conditions and Their Impact among Adolescents and Young Adults with Down Syndrome

Objective: To examine the prevalence of medical conditions and use of health services among young adults with Down syndrome and describe the impact of these conditions upon their lives. Methods: Using questionnaire data collected in 2011 from parents of young adults with Down syndrome we investigated the medical conditions experienced by their children in the previous 12 months. Univariate, linear and logistic regression analyses were performed. Results: We found that in addition to the conditions commonly experienced by children with Down syndrome, including eye and vision problems (affecting 73%), ear and hearing problems (affecting 45%), cardiac (affecting 25%) and respiratory problems (affecting 36%), conditions also found to be prevalent within our young adult cohort included musculoskeletal conditions (affecting 61%), body weight (affecting 57%), skin (affecting 56%) and mental health (affecting 32%) conditions and among young women menstrual conditions (affecting 58%). Few parents reported that these conditions had no impact, with common impacts related to restrictions in opportunities to participate in employment and community leisure activities for the young people, as well as safety concerns. Conclusion: There is the need to monitor, screen and provide appropriate strategies such as through the promotion of healthy lifestyles to prevent the development of comorbidities in young people with Down syndrome and, where present, to reduce their impact