Differential effect of Incobotulinumtoxin A on pain, neurogenic flare and hyperalgesia in human surrogate models of neurogenic pain.

BACKGROUND: The effectiveness of Botulinum-neurotoxin A (BoNT/A) to treat pain in human pain models is very divergent. This study was conducted to clarify if the pain models or the route of BoNT/A application might be responsible for these divergent findings. METHODS: Sixteen healthy subjects (8 males, mean age 27 ± 5 years) were included in a first set of experiments consisting of three visits: (1) Visit: Quantitative sensory testing (QST) was performed before and after intradermal capsaicin injection (CAPS, 15 µg) on one thigh and electrical current stimulation (ES, 1 Hz) on the contralateral thigh. During stimulation pain and the neurogenic flare response (laser-Doppler imaging) were assessed. (2) Four weeks later, BoNT/A (Xeomin® , 25 MU) was injected intracutaneously on both sides. (3) Seven days later, the area of BoNT/A application was determined by the iodine-starch staining and the procedure of the (1) visit was exactly repeated. In consequence of these results, 8 healthy subjects (4 males, mean age 26 ± 3 years) were included into a second set of experiments. The experimental setting was exactly the same with the exception that stimulation frequency of ES was increased to 4 Hz and BoNT/A was injected subcutaneously into the thigh, which was stimulated by capsaicin. RESULTS: BoNT/A reduced the 1 Hz ES flare size (p < 0.001) and pain ratings (p < 0.01), but had no effect on 4 Hz ES and capsaicin-induced pain, hyperalgesia, or flare size, regardless of the depth of BoNT/A injection (i.c./s.c). Moreover, i.c. BoNT/A injection significantly increased warm detection and heat pain thresholds in naive skin (WDT, Δ 2.2 °C, p < 0.001; HPT Δ 1.8 °C, p < 0.005). CONCLUSION: BoNT/A has a moderate inhibitory effect on peptidergic and thermal C-fibers in healthy human skin. SIGNIFICANCE: The study demonstrates that BoNT/A (Incobotulinumtoxin A) has differential effects in human pain models: It reduces the neurogenic flare and had a moderate analgesic effects in low frequency but not high frequency current stimulation of cutaneous afferent fibers at C-fiber strength; BoNT/A had no effect in capsaicin-induced (CAPS) neurogenic flare or pain, or on hyperalgesia to mechanical or heat stimuli in both pain models. Intracutaneous BoNT/A increases warm and heat pain thresholds on naïve skin.

Steel slags in a landfill top cover--experiences from a full-scale experiment.

A full scale field study has been carried out in order to test and evaluate the use of slags from high-alloy steel production as the construction materials for a final cover of an old municipal landfill. Five test areas were built using different slag mixtures within the barrier layer (liner). The cover consisted of a foundation layer, a liner with a thickness of 0.7 m, a drainage layer of 0.3 m, a protection layer of 1.5 m and a vegetation layer of 0.25 m. The infiltration varied depending on the cover design used, mainly the liner recipe but also over time and was related to seasons and precipitation intensity. The test areas with liners composed of 50% electric arc furnace (EAF) slag and 50% cementitious ladle slag (LS) on a weight basis and with a proper consistence of the protection layer were found to meet the Swedish infiltration criteria of ⩽50 l (m(2)a)(-1) for final covers for landfills for non-hazardous waste: the cumulative infiltration rates to date were 44, 19 and 0.4 l (m(2)a)(-1) for A1, A4 and A5, respectively. Compared to the precipitation, the portion of leachate was always lower after the summer despite high precipitation from June to August. The main reason for this is evapotranspiration but also the fact that the time delay in the leachate formation following a precipitation event has a stronger effect during the shorter summer sampling periods than the long winter periods. Conventional techniques and equipment can be used but close cooperation between all involved partners is crucial in order to achieve the required performance of the cover. This includes planning, method and equipment testing and quality assurance.

Brain activation during fear conditioning in humans depends on genetic variations related to functioning of the hypothalamic-pituitary-adrenal axis: first evidence from two independent subsamples.

BACKGROUND: Enhanced acquisition and delayed extinction of fear conditioning are viewed as major determinants of anxiety disorders, which are often characterized by a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis. METHOD: In this study we employed cued fear conditioning in two independent samples of healthy subjects (sample 1: n=60, sample 2: n=52). Two graphical shapes served as conditioned stimuli and painful electrical stimulation as the unconditioned stimulus. In addition, guided by findings from published animal studies on HPA axis-related genes in fear conditioning, we examined variants of the glucocorticoid receptor and corticotropin-releasing hormone receptor 1 genes. RESULTS: Variation in these genes showed enhanced amygdala activation during the acquisition and reduced prefrontal activation during the extinction of fear as well as altered amygdala-prefrontal connectivity. CONCLUSIONS: This is the first demonstration of the involvement of genes related to the HPA axis in human fear conditioning.

[Acute illness and depression in the elderly and the influence of cognitive impairment : AIDE-cog trial]. / Komorbidität von Depression und Demenz bei geriatrischen Patienten mit akuter körperlicher Erkrankung: AIDE-cog-Studie.

Geriatric patients with acute somatic illness have a high comorbidity of depression and dementia. The following differential diagnoses have to be discerned: pseudodementia in acute depressive states, depression as a risk factor for dementia, and a depressive episode in the early stage of dementia. For both the symptoms and the trigger factors of these differential diagnoses the overlap and the particularities were qualitatively examined in the AIDE-cog (Acute Illness and Depression in Elderly cognition) trial. A second prospective randomized controlled part of the AIDE-cog trial quantitatively evaluated the influence of cognitive impairment in geriatric patients with an acute somatic illness and comorbid depression on the therapeutic effect of cognitive behavioral therapy. A preliminary analysis shows that already in early dementia the therapeutic effects are inferior. Other psychotherapeutic methods that address the remaining cognitive and emotional functions in dementia must be evaluated.

Accelerated carbonation of steel slags in a landfill cover construction.

Steel slags from high-alloyed tool steel production were used in a full scale cover construction of a municipal solid waste (MSW) landfill. In order to study the long-term stability of the steel slags within the final cover, a laboratory experiment was performed. The effect on the ageing process, due to i.e. carbonation, exerted by five different factors resembling both the material characteristics and the environmental conditions is investigated. Leaching behaviour, acid neutralization capacity and mineralogy (evaluated by means of X-ray diffraction, XRD, and thermogravimetry/differential thermal analysis, TG/DTA) are tested after different periods of ageing under different conditions. Samples aged for 3 and 10 months were evaluated in this paper. Multivariate data analysis was used for data evaluation. The results indicate that among the investigated factors, ageing time and carbon dioxide content of the atmosphere were able to exert the most relevant effect. However, further investigations are required in order to clarify the role of the temperature.

Characterization of the protein processing and secretion pathways in a comprehensive set of expressed sequence tags from Trichoderma reesei.

Trichoderma reesei is a filamentous fungus widely used as an efficient protein producer and known to secrete large quantities of biomass degrading enzymes. Much work has been done aimed at improving the secretion efficiency of this fungus. It is generally accepted that the major bottlenecks in secretion are protein folding and ornamentation steps in this pathway. In an attempt to identify genes involved in these steps, the 5' ends of 21888 cDNA clones were sequenced from which a unique set of over 5000 were also 3' sequenced. Using annotation tools Gene Ontology terms were assigned to 2732 of the sequences. Homologs to the majority of Aspergillus niger's Srg genes as well as a number of homologs to genes involved in protein folding and ornamentation pathways were identified.

Morphologic analysis of human lymphokine-activated killer (LAK) cells.

Lymphokine-activated killer (LAK) cells obtained from normal donors at various days of in vitro cultivation have been studied by several methods including scanning (SEM) and transmission (TEM) electron microscopy, immuno-electron microscopy, in situ hybridization and flow cytometric DNA measurements. In addition, the cytotoxic activity of LAK cells against several tumor cells was examined by 51Cr-release assay and by SEM and TEM. The LAK cells displayed a uniform ultrastructural appearance concerning surface structure and morphology of organelles. They contained typical lysosomal granules which by immuno-electron microscopy showed a specific localization of perforin I (PI). The presence of PI and granzymeA mRNA in the cytoplasm was confirmed by in situ hybridization using specific antisense probes. Frequency and increased of specific mRNA-containing cells was similar for both genes. Single LAK cells were further characterized by peculiar nuclear inclusion bodies (IB) which were presumably formed by trapped profiles of endoplasmic reticulum. Flow cytometric analysis revealed normal DNA content of LAK cells even after prolonged cultivation indicating that the IB were not associated with aneuploidy of the effector cells. The LAK cells were highly effective in lysing K562 and DAUDI cells as shown by 51Cr-release assay. They caused characteristic morphologic alterations of target cells similar to those found in cytotoxic T-lymphocyte (CTL) and NK-cell-mediated cytolysis. SEM and TEM studies on specimens prepared by routine procedures or by cryopreparation showed that the tumor cell membrane was the initial target for the LAK cell attack whereas other cell compartments were damaged only in advanced stages of cytolysis. Summarizing our study demonstrates that LAK cells have a characteristic ultrastructure which in some aspects differs from that of CTL and NK cells, and that LAK cells appear to destroy tumor cells by mechanisms similar to those of other cytotoxic effector cells.