| 2051. |
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| 2052. |
- Petzke, F, et al.
(författare)
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Using fMRI to evaluate the effects of milnacipran on central pain processing in patients with fibromyalgia.
- 2013
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Ingår i: Scandinavian Journal of Pain. - : Walter de Gruyter GmbH. - 1877-8860 .- 1877-8879. ; 4:2, s. 65-74
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Tidskriftsartikel (refereegranskat)abstract
- Background In recent years, the prescription of serotonin-noradrenalin reuptake inhibitors (SNRIs) for treatment of fibromyalgia (FM) has increased with reports of their efficacy. The SNRI milnacipran is approved by the U.S. Food and Drug Administration (FDA) for treatment of FM, yet, the mechanisms by which milnacipran reduces FM symptoms are unknown. A large number of neuroimaging studies have demonstrated altered brain function in patients with FM but the effect of milnacipran on central pain processing has not been investigated. The primary objective of this study was to assess the effect of milnacipran on sensitivity to pressure-evoked pain in FM. Secondary objectives were to assess the effect of milnacipran on cerebral processing of pressure-evoked pain using fMRI and the tolerability and safety of milnacipran 200 mg/day in FM. Methods 92 patients were randomized to either 13-weeks milnacipran treatment (200 mg/day) or placebo in this double-blind, placebo-controlled multicenter clinical trial. Psychophysical measures and functional MRI (fMRI) assessments were performed before and after treatment using a computer-controlled pressure-pain stimulator. Here, we present the results of several a priori defined statistical analyses. Results Milnacipran-treated patients displayed a trend toward lower pressure-pain sensitivity after treatment, compared to placebo, and the difference was greater at higher pain intensities. A single group fMRI analysis of milnacipran-treated patients indicated increased pain-evoked brain activity in the caudatus nucleus, anterior insula and amygdala after treatment, compared to before treatment; regions implicated in pain inhibitory processes. A 2 × 2 repeated measures fMRI analysis, comparing milnacipran and placebo, before and after treatment, showed that milnacipran-treated patients had greater pain-evoked activity in the precuneus/posterior cingulate cortex after treatment; a region previously implicated in intrinsic brain function and FM pathology. This finding was only significant when uncorrected for multiple comparisons. The safety analysis revealed that patients from both treatment groups had treatment-emergent adverse events where nausea was the most common complaint, reported by 43.5% of placebo patients and 71.7% of milnacipran-treated patients. Patients on milnacipran were more likely to discontinue treatment because of side effects. Conclusions Our results provide preliminary indications of increased pain inhibitory responses in milnacipran-treated FM patients, compared to placebo. The psychophysical assessments did not reach statistical significance but reveal a trend toward higher pressure-pain tolerance after treatment with milnacipran, compared to placebo, especially for higher pain intensities. Our fMRI analyses point toward increased activation of the precuneus/posterior cingulum in patients treated with milnacipran, however results were not corrected for multiple comparisons. The precuneus/posterior cingulum is a key region of the default mode network and has previously been associated with abnormal function in FM. Future studies may further explore activity within the default mode network as a potential biomarker for abnormal central pain processing. Implications The present study provides novel insights for future studies where functional neuroimaging may be used to elucidate the central mechanisms of common pharmacological treatments for chronic pain. Furthermore, our results point toward a potential mechanism for pain normalization in response to milnacipran, involving regions of the default mode network although this finding needs to be replicated in future studies.
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| 2053. |
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| 2054. |
- Phillips, C. L., et al.
(författare)
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The effect of short-term withdrawal from continuous positive airway pressure therapy on sympathetic activity and markers of vascular inflammation in subjects with obstructive sleep apnoea
- 2007
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Ingår i: J Sleep Res. - 0962-1105. ; 16:2, s. 217-25
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Tidskriftsartikel (refereegranskat)abstract
- Obstructive sleep apnoea (OSA) is commonly associated with cardiovascular disease and sympathetic activation. However, it is unclear whether this association is independent of obesity and to what extent treatment with nasal continuous positive airway pressure (CPAP) alleviates the vascular inflammation that underpins cardiovascular disease. We therefore evaluated whether short-term withdrawal from CPAP therapy in subjects with moderate-severe OSA would result in increased levels of sympathetic activity and circulating inflammatory cytokines independent of weight. Vascular inflammatory markers (hsCRP, hsIL-6 and hsTNF-alpha) were assessed in 20 subjects after one and seven nights of withdrawal from CPAP together with the hypoxia-responsive angiogenic marker VEGF and urinary catecholamines. Compared with baseline on CPAP, withdrawal from therapy resulted in an immediate return of OSA with an increase in RDI to 26.7 +/- 5.2 and 39.0 +/- 5.9 events per hour after one and seven nights without CPAP, respectively (both P < 0.0001). This was accompanied by a concomitant rise in daytime urinary noradrenaline (P < 0.0001) after seven nights CPAP withdrawal that was positively associated with the severity of hypoxaemia. In contrast, withdrawal from CPAP therapy was not accompanied by any change in measured cytokines or VEGF (all P > 0.1). In conclusion, 1 week of CPAP withdrawal was associated with a return of OSA and a marked increase in sympathetic activity without a concomitant elevation of vascular inflammatory markers.
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| 2055. |
- Plane, John M. C., et al.
(författare)
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A combined rocket-borne and ground-based study of the sodium layer and charged dust in the upper mesosphere
- 2014
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Ingår i: Journal of Atmospheric and Solar-Terrestrial Physics. - : Elsevier BV. - 1364-6826 .- 1879-1824. ; 118, s. 151-160
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Tidskriftsartikel (refereegranskat)abstract
- The Hotel Payload 2 rocket was launched on January 31st 2008 at 20.14 LT from the Andoya Rocket Range in northern Norway (69.31 degrees N, 16.01 degrees E). Measurements in the 75-105 km region of atomic O, negatively-charged dust, positive ions and electrons with a suite of instruments on the payload were complemented by lidar measurements of atomic Na and temperature from the nearby ALOMAR observatory. The payload passed within 2.58 km of the lidar at an altitude of 90 km. A series of coupled models is used to explore the observations, leading to two significant conclusions. First, the atomic Na layer and the vertical profiles of negatively-charged dust (assumed to be meteoric smoke particles), electrons and positive ions, can be modelled using a self-consistent meteoric input flux. Second, electronic structure calculations and Rice-Ramsperger-Kassel-Markus theory are used to show that even small Fe-Mg-silicates are able to attach electrons rapidly and form stable negatively-charged particles, compared with electron attachment to O-2 and O-3. This explains the substantial electron depletion between 80 and 90 km, where the presence of atomic O at concentrations in excess of 10(10) cm(-3) prevents the formation of stable negative ions.
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| 2056. |
- Platt, A, et al.
(författare)
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The 4-hydroxy-2-oxovalerate aldolase and acetaldehyde dehydrogenase (acylating) encoded by the nahM and nahO genes of the naphthalene catabolic plasmid pWW60-22 provide further evidence of conservation of meta-cleavage pathway gene sequences.
- 1995
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Ingår i: Microbiology. - : Microbiology Society. - 1350-0872 .- 1465-2080. ; 141 ( Pt 9)
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Tidskriftsartikel (refereegranskat)abstract
- We report the complete nucleotide sequence and over-expression of the nahOM genes for the acetaldehyde dehydrogenase (acylating) and the 4-hydroxy-2-oxovalerate aldolase from the meta pathway operon of the naphthalene catabolic plasmid pWW60-22 from Pseudomonas sp. NCIMB9816. Additional partial sequence analysis of adjacent DNA shows the gene order within the operon to be nahNLOMK, identical to the order found for the isofunctional genes in the meta pathway operons in the toluene/xylene pathway of TOL plasmid pWW0 and the phenol/methylphenol pathway of pVI150. The deduced amino acid sequences of NahO and NahM were significantly homologous to the equivalent enzymes encoded by other Pseudomonas meta pathways, although both were the most divergent in each comparison. The nahOM genes were inserted downstream of the T7 promoter in the expression vector pET3a and similar constructs were also made of the isofunctional regions from pVI150 (dmpFG) and TOL plasmid pDK1 (xyIQK). High expression of all three gene pairs was detected by enzyme assays and by SDS-PAGE.
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| 2057. |
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| 2058. |
- Popp, David, et al.
(författare)
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Flow-aligned, single-shot fiber diffraction using a femtosecond X-ray free-electron laser
- 2017
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Ingår i: CYTOSKELETON. - : WILEY. - 1949-3584 .- 1949-3592. ; 74:12, s. 472-481
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Tidskriftsartikel (refereegranskat)abstract
- A major goal for X-ray free-electron laser (XFEL) based science is to elucidate structures of biological molecules without the need for crystals. Filament systems may provide some of the first single macromolecular structures elucidated by XFEL radiation, since they contain one-dimensional translational symmetry and thereby occupy the diffraction intensity region between the extremes of crystals and single molecules. Here, we demonstrate flow alignment of as few as 100 filaments (Escherichia coli pili, F-actin, and amyloid fibrils), which when intersected by femtosecond X-ray pulses result in diffraction patterns similar to those obtained from classical fiber diffraction studies. We also determine that F-actin can be flow-aligned to a disorientation of approximately 5 degrees. Using this XFEL-based technique, we determine that gelsolin amyloids are comprised of stacked -strands running perpendicular to the filament axis, and that a range of order from fibrillar to crystalline is discernable for individual -synuclein amyloids.
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| 2059. |
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| 2060. |
- Probert, Christopher S J, et al.
(författare)
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The effect of weaning on the clonality of alpha beta T-cell receptor T cells in the intestine of GF and SPF mice.
- 2007
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Ingår i: Developmental and comparative immunology. - : Elsevier BV. - 0145-305X. ; 31:6, s. 606-17
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Tidskriftsartikel (refereegranskat)abstract
- In humans, intestinal antigen exposure during neonatal life influences the T-cell receptor (TCR) repertoire. To define the relative effects of bacteria and food antigens in early life, we examined TCR diversity in the intestine of SPF and GF mice. TCR repertoire was assessed at a single time point pre-, peri- and post-weaning in the small and large intestine of SPF and GF mice using spectratyping and/or TCR-beta-chain sequencing. There was good concordance of data obtained by the two techniques. In SPF mice, the repertoire was polyclonal shortly after birth in the small and large intestine. After weaning, there was a significant change towards an oligoclonal repertoire in the small intestine. There was some evidence that specific clones were shared between the small and large intestine. In contrast, in GF mice, the repertoire was oligoclonal after birth, and remained restricted. These data show: firstly, that under SPF conditions, the intestine is seeded with a diverse T-cell population that becomes oligoclonal around the time of weaning; secondly, that GF mice were oligoclonal at each time point.
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