378 research outputs found
Prosaptide prevents paclitaxel neurotoxicity
No full textPaclitaxel (Taxol(TM)), a chemotherapeutic agent used to treat breast and ovarian tumors, has been reported to induce a predominantly sensory neuropathy. Co-treatment with neurotrophic factors and paclitaxel has been proposed for preventing or reversing paclitaxel induced peripheral neuropathy. Prosaposin, the precursor of saposins A, B, C and D was recently identified as a neurotrophic factor and was reported to facilitate nerve regeneration in vivo. Peptides (prosaptides) encompassing the neurotrophic sequence located in the saposin C domain, have neurotrophic activity similar to the holoprotein (O'Brien et al. 1995). In the present study, we investigated the effect of a 14-mer prosaptide, TX14(A), or a 22- merprosaptide, 769P, on paclitaxel-induced neurotoxicity in vitro and in vivo. Paclitaxel treatment (1 μM) decreased cell viability of both PC12 and Schwann cells. TX14(A) (10 nM) prevented paclitaxel-induced loss of cell viability in PC12 cells but not in Schwann cells. Systemic injections (i.p.) of paclitaxel (1.2 mg/kg/day) given five times per week for three weeks (cumulative dose 18 mg/kg) or given every third day (25, 12.5 and 12.5 mg/kg) for 10 ten days (cumulative dose 50 mg/kg) in adult rats induced thermal hypoalgesia that was not accompanied by morphological changes in the sciatic nerve or changes of nerve conduction velocity. Co-administration of paclitaxel with prosaptides (cumulative dose 3 or 10 mg/kg) prevented paclitaxel-induced thermal hypoalgesia. In the short-term high dose study, paclitaxel treated rats lost 10% of their body weight, had reduced erythrocyte counts, hematocrit and hemoglobin concentrations which were not prevented by treatment with prosaptide. TX14(A) did not diminish paclitaxel cytotoxicity of breast cancer cells in vitro. These findings suggest that prosaptide prevents the neurotoxic effects of paclitaxel while not interfering with its anti-tumor activity
Spinal Inhibitory Dysfunction in Patients With Painful or Painless Diabetic Neuropathy
No full textOBJECTIVE: Impaired rate-dependent depression of the Hoffman reflex (HRDD) is a marker of spinal inhibitory dysfunction and has previously been associated with painful neuropathy in a proof-of-concept study in patients with type 1 diabetes. We have now undertaken an assessment of HRDD in patients with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 148 participants, including 34 healthy control subjects, 42 patients with painful diabetic neuropathy, and 62 patients with diabetic neuropathy without pain, underwent an assessment of HRDD and a detailed assessment of peripheral neuropathy, including nerve conduction studies, corneal confocal microscopy, and thermal threshold testing. RESULTS: Compared with healthy control subjects (P < 0.001) and patients without pain (P < 0.001), we found that HRDD is impaired in patients with type 1 or type 2 diabetes with neuropathic pain. These impairments are unrelated to diabetes type and the presence or severity of neuropathy. In contrast, patients without neuropathic pain (P < 0.05) exhibited enhanced HRDD compared with control subjects. CONCLUSIONS: We suggest that loss or impairment of HRDD may help to identify a subpopulation of patients with painful diabetic neuropathy mediated by impaired spinal inhibitory systems who may respond optimally to therapies that target spinal or supraspinal mechanisms. Enhanced RDD in patients without pain may reflect engagement of spinal pain-suppressing mechanisms
Prosaposin-derived peptides enhanced sprouting of sensory neurons in vitro and induced sprouting at motor endplates in vivo
No full textProsaposin exhibits neurotrophic factor properties that are localized to a 12-amino acid sequence located in the amino terminal portion of the saposin C domain. Prosaptides are peptides derived from the neurotrophic portion of prosaposin; these have been previously reported to be bioactive in neuroblastoma cell lines in vitro. We report that prosaptides were also bioactive in explants of adult primary sensory neurons by dose-dependently increasing both the number (3- to 4-fold) and elongation of these neurites by 50%. Local injection of prosaptides into the gluteus muscle of adult mice also induced sprouting at the motor endplate. Our results indicate that prosaptides are potent neuritogenic factors for both sensory and motor neurons of adult peripheral nerve
Optimal utility of h-reflex rdd as a biomarker of spinal disinhibition in painful and painless diabetic neuropathy
No full textImpaired rate-dependent depression of the Hoffman reflex (HRDD) is a potential biomarker of impaired spinal inhibition in patients with painful diabetic neuropathy. However, the optimum stimulus-response parameters that identify patients with spinal disinhibition are currently unknown. We systematically compared HRDD, performed using trains of 10 stimuli at five stimulation frequencies (0.3, 0.5, 1, 2 and 3 Hz), in 42 subjects with painful and 62 subjects with painless diabetic neuropathy with comparable neuropathy severity, and 34 healthy controls. HRDD was calculated using individual and mean responses compared to the initial response. At stimulation frequencies of 1, 2 and 3 Hz, HRDD was significantly impaired in patients with painful diabetic neuropathy compared to patients with painless diabetic neuropathy for all parameters and for most parameters when compared to healthy controls. HRDD was significantly enhanced in patients with painless diabetic neuropathy compared to controls for responses towards the end of the 1 Hz stimulation train. Receiver operating characteristic curve analysis in patients with and without pain showed that the area under the curve was greatest for response averages of stimuli 2–4 and 2–5 at 1 Hz, AUC = 0.84 (95%CI 0.76–0.92). Trains of 5 stimuli delivered at 1 Hz can segregate patients with painful diabetic neuropathy and spinal disinhibition, whereas longer stimulus trains are required to segregate patients with painless diabetic neuropathy and enhanced spinal inhibition
Characterising Saturn's vertical temperature structure from Cassini/CIRS
No full textThermal infrared spectra of Saturn from 10-1400 cm-1 at 15 cm-1 spectral resolution and a spatial resolution of 1°-2° latitude have been obtained by the Cassini Composite Infrared Spectrometer [Flasar, F.M., and 44 colleagues, 2004. Space Sci. Rev. 115, 169-297]. Many thousands of spectra, acquired over eighteen-months of observations, are analysed using an optimal estimation retrieval code [Irwin, P.G.J., Parrish, P., Fouchet, T., Calcutt, S.B., Taylor, F.W., Simon-Miller, A.A., Nixon, C.A., 2004. Icarus 172, 37-49] to retrieve the temperature structure and para-hydrogen distribution over Saturn's northern (winter) and southern (summer) hemispheres. The vertical temperature structure is analysed in detail to study seasonal asymmetries in the tropopause height (65-90 mbar), the location of the radiative-convective boundary (350-500 mbar), and the variation with latitude of a temperature knee (between 150 and 300 mbar) which was first observed in inversions of Voyager/IRIS spectra [Hanel, R., and 15 colleagues, 1981. Science 212, 192-200; Hanel, R., Conrath, B., Flasar, F.M., Kunde, V., Maguire, W., Pearl, J.C., Pirraglia, J., Samuelson, R., Cruikshank, D.P., Gautier, D., Gierasch, P.J., Horn, L., Ponnamperuma, C., 1982. Science 215, 544-548]. Uncertainties due to both the modelling of spectral absorptions (collision-induced absorption coefficients, tropospheric hazes, helium abundance) and the nature of our retrieval algorithm are quantified. Temperatures in the stratosphere near 1 mbar show a 25-30 K temperature difference between the north pole and south pole. This asymmetry becomes less pronounced with depth as the radiative time constant for the atmospheric response increases at deeper pressure levels. Hemispherically-symmetric small-scale temperature structures associated with zonal winds are superimposed onto the temperature asymmetry for pressures greater than 100 mbar. The para-hydrogen fraction in the 100-400 mbar range is greater than equilibrium predictions for the southern hemisphere and parts of the northern hemisphere, and less than equilibrium predictions polewards of 40° N. The temperature knee between 150-300 mbar is larger in the summer hemisphere than in the winter, smaller and higher at the equator, deeper and larger in the equatorial belts and small at the poles. Solar heating on tropospheric haze is proposed as a possible mechanism for this effect; the increased efficiency of ortho- to para-hydrogen conversion in the southern hemisphere is consistent with the presence of larger aerosols in the summer hemisphere, which we demonstrate to be qualitatively consistent with previous studies of Saturn's tropospheric aerosol distribution. © 2007 Elsevier Inc. All rights reserved
An analysis of the NET1 proteins: a group of novel plant actin-binding proteins
No full textThe NET protein superfamily is a recently discovered family of novel, plant-specific actin binding proteins. The identification of this family represents a significant discovery as the plant cytoskeleton is not identical to the animal cytoskeleton and plant cells show plant specific processes and subcellular structures which rely on actin. There is a need for plant specific proteins which are capable of modelling actin within plant cells.
The NET family comprises thirteen proteins in Arabidopsis thaliana, which share the NET actin binding domain (found at the N-terminal end of each protein). Based on the C-terminal domains of the proteins, the family can be separated into four groups, each with a particular localisation. The localisations of these proteins are frequently within plant specific cell types, such as pollen tubes, guard cells or roots, or to plant specific cell structures such as plasmodesmata. It is thought that these proteins may be involved in modelling the actin cytoskeleton at junctions between actin and membranes (either cell membranes or membrane bound structures such as the endoplasmic reticulum).
The NET1 proteins are a group of four proteins, each consisting of an N-terminal actin binding domain and C-terminal coiled-coil domains. NET1a was the first protein to be discovered in a high-throughput screen of plant proteins for novel localisations carried out by Karl Oparka, where it was shown to bind to filaments. Work by Calcutt (Calcutt 2009) showed the filaments to be the actin cytoskeleton.
The aim of this thesis has been to complete the characterisation of all Group 1 NET proteins, building on the analysis of NET1a by Calcutt (Calcutt 2009) and to investigate the possible functions of the NET1 subfamily proteins. All four proteins have been shown to be capable of actin binding and to be expressed in, and locate to structures within, the roots of A. thaliana. NET1a has been linked to plasmodesmata, and the combined absence of NET1a and NET1b in the plant results in a cumulative, long root phenotype. Theories to explain this phenotype are suggested here, although the validation and testing of these will form the basis of future work
Line-by-line analysis of Neptune's near-IR spectrum observed with Gemini/NIFS and VLT/CRIRES
No full textNew line data describing the absorption of CH4 and CH3D from 1.26 to 1.71μm (WKMC-80K, Campargue, A., Wang, L., Mondelain, D., Kassi, S., Bézard, B., Lellouch, E., Coustenis, A., de Bergh, C., Hirtzig, M., Drossart, P. [2012]. Icarus 219, 110-128) have been applied to the analysis of Gemini-N/NIFS observations of Neptune made in 2009 and VLT/CRIRES observations made in 2010. The new line data are found to greatly improve the fit to the observed spectra and present a considerable advance over previous methane datasets. The improved fits lead to an empirically derived wavelength-dependent correction to the scattering properties of the main observable cloud deck at 2-3bars that is very similar to the correction determined for Uranus' lower cloud using the same line dataset by Irwin et al. (Irwin, P.G.J., de Bergh, C., Courtin, R., Bézard, B., Teanby, N.A., Davis, G.R., Fletcher, L.N., Orton, G.S., Calcutt, S.B., Tice, D., Hurley, J. [2012]. Icarus 220, 369-382). By varying the abundance of CH3D in our simulations, analysis of the Gemini/NIFS observations leads to a new determination of the CH3D/CH4 ratio for Neptune of 3.0-0.9+1.0×10-4, which is smaller than previous determinations, but is identical (to within error) with the CH3D/CH4 ratio of 2.9-0.5+0.9×10-4 derived by a similar analysis of Gemini/NIFS observations of Uranus made in the same year. Thus it appears that the atmospheres of Uranus and Neptune have an almost identical D/H ratio, which suggests that the icy planetisimals forming these planets came from the same source reservoir, or a reservoir that was well-mixed at the locations of ice giant formation, assuming complete mixing between the atmosphere and interior of both these planets. VLT/CRIRES observations of Neptune have also been analysed with the WKMC-80K methane line database, yielding very good fits, with little evidence for missing absorption features. The CRIRES spectra indicate that the mole fraction of CO at the 2-3bar level must be substantially less than its estimated stratospheric value of 1×10-6, which suggests that the predominant source of CO in Neptune's atmosphere is external, through the influx of micrometeorites and comets, although these data cannot rule out an additional internal source. © 2013 Elsevier Inc
Descriptive analysis of a 1:1 physiotherapy outpatient intervention post primary lumbar discectomy: one arm of a small-scale parallel randomised controlled trial across two UK sites
No full textObjective: There is a lack of high-quality evidence for physiotherapy post lumbar discectomy. Substantial heterogeneity in treatment effects may be explained byvariation in quality, administration and components of interventions. An optimised physiotherapy intervention may reduce heterogeneity and improve patient benefit. The objective was to describe, analyse and evaluate anoptimised 1:1 physiotherapy outpatient intervention for patients following primary lumbar discectomy, to provide preliminary insights.Design: A descriptive analysis of the intervention embedded within an external pilot and feasibility trial.Setting: Two UK spinal centres.Participants: Participants aged ≥18; post primary, single level, lumbar discectomy were recruited.Intervention: The intervention encompassed education, advice, mobility and core stability exercises, progressive exercise, and encouragement of early return to work/activity. Patients received ≤8 sessions for ≤8 weeks, starting 4 weeks post surgery (baseline).Outcomes: Blinded outcome assessment at baseline and 12 weeks ( post intervention) included the Roland Morris Disability Questionnaire. STarT Backdata were collected at baseline. Statistical analyses summarised participant characteristics and preplanned descriptive analyses. Thematic analysisgrouped related data.Findings: Twenty-two of 29 allocated participants received the intervention. STarT Back categorised n=16 (55%) participants ‘not at low risk’. Physiotherapists identified reasons for caution for 8 (36%) participants, commonly risk of overdoing activity (n=4, 18%). There was no relationship between STarT Back and physiotherapists’ evaluation of caution. Physiotherapists identified 154 problems (mean (SD) 5.36 (2.63)). Those ‘not at low risk’, and/or requiring caution presented with more problems, and required more sessions (mean (SD) 3.14 (1.16)).Conclusions: Patients present differently and therefore require tailored interventions. These differences may be identified using clinical reasoningand outcome data. Trial registration number: ISRCTN33808269; postresults
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