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  • 1
    ISSN: 1619-1560
    Keywords: clonidine ; sympathetic nervous system ; blood pressure monitoring ; hypotension
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study assessed the effects of clonidine on blood pressure (BP) and heart rate responses to active standing, recorded continuously using a Finapres monitor. Ten subjects were given a placebo infusion over 1 h, followed by clonidine hydrochloride 1.5 µg/kg over 2 h. During placebo and at 1, 3 and 19 h following the clonidine infusion, heart rate and blood pressure were recorded during the second half of supine rest for 10 min, active standing and quiet standing for 7 min. Clonidine did not alter the size of immediate drop in BP on standing, although the nadir was lower. BP recovery was impaired, with a loss of the usual BP overshoot in most subjects and with delays in reaching supine levels of diastolic BP (6.1 versus 9.6 s; p 〈 0.01) and systolic BP (8.1 versus 12.3 s; p 〈 0.05). The compensatory initial heart rate rise was significantly increased from 47 to 53 beats/min (p 〈 0.05), athough the peak rate reached was reduced from 114 to 104 beats/min (p 〈 0.05). These results demonstrate that impairment of central sympathetic vasomotor drive leads to a delay in BP recovery and loss of initial BP overshoot immediately after standing, together with impaired maintenance of early steady-state BP.
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  • 2
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background Allergic inflammation is characterized by the influx and activation of eosinophils. Cytokines generated by both resident and infiltrating cells are responsible for the initiation and maintenance of this pathogenesis. This study focuses on allergen-induced activation of eosinophil NF-κB and generation of granulocyte macrophage-colony stimulating factor (GM-CSF), TNF-α, and IL-8.Methods Peripheral blood eosinophils were enriched to 〉99.9% by Percoll gradient sedimentation and negative magnetic affinity chromatography. NF-κB activation by 10 μg/mL house dust mite (HDM) extract was demonstrated immunocytochemically using a monoclonal antibody against the active form of NF-κB (NF-κBa). The authenticity of NF-κB was confirmed by Western blot. Cytokine production was assessed both by immuno-staining of eosinophils and by assay of cytokines in the cell supernatant.Results Activation of peripheral blood eosinophils from atopic, but not non-atopic, donors induced activation of NF-κB, which peaked at 4 h and was accompanied by a decline in IκB-α. The activation of authentic NF-κB was confirmed in gel shift assays. Supershift assays showed p65 to be the major subunit of eosinophil NF-κB. Immunofluorescent confocal microscopy demonstrated localization of NF-κBa to the nucleus. Following activation, cytokine immunoreactivity was seen in a fraction of the eosinophils and cytokines were released into the supernatant. The NF-κB inhibitors, calpain inhibitor 1 (10 μm), pentoxifylline (0.5 mm), pyrrolidine dithiocarbamate (PDTC, 10 μm) or gliotoxin (1 pg/mL) reduced the generation of GM-CSF, TNF-α and IL-8 in parallel with their inhibition of NF-κB.Conclusions HDM allergen activates human eosinophil NF-κB leading to the production of the cytokines GM-CSF, TNF-α and IL-8. We speculate that a role for eosinophil NF-κB-dependent cytokines is to act as an autocrine loop augmenting the survival of eosinophils in vivo.
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Studies of the pathology of rhinitis and asthma have identified similarities and differences between these two clinical conditions. With regard to symptoms, both the nose and the lower airways respond to neural stimulation by irritant substances, but a major difference is that engorgement of the capacitance vessels is the main cause of nasal obstruction in rhinitis, while muscle constriction is the major determinant of lower airway narrowing. There are also similarities and differences with respect to the role of infiammatory cells. In both conditions there is evidence of allergen-induced mast cell activation, with production of an array of mediators (some mast cell-derived and others originating from a variety of other cell types). Eosinophilia is also characteristic of both diseases — it is prominent even in mild forms of asthma, but is low in pollen-sensitive rhinitics outside of the season. T-cell activation and production of cytokines plays an important role in the development and maintenance of allergic disease, but the level of T-cell activation may differ between asthma and rhinitis. Further research into differences in cellular activity and response to treatment between these two diseases may help define factors which will determine whether atopic disease is expressed in the upper, lower, or both parts of the respiratory tract.
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  • 4
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background The extent of epithelial injury in asthma is reflected by expression of the epidermal growth factor receptor (EGFR), which is increased in proportion to disease severity and is corticosteroid refractory. Although the EGFR is involved in epithelial growth and differentiation, it is unknown whether it also contributes to the inflammatory response in asthma.Objectives Because severe asthma is characterized by neutrophilic inflammation, we investigated the relationship between EGFR activation and production of IL-8 and macrophage inhibitory protein-1 alpha (MIP-1α) using in vitro culture models and examined the association between epithelial expression of IL-8 and EGFR in bronchial biopsies from asthmatic subjects.Methods H292 or primary bronchial epithelial cells were exposed to EGF or H2O2 to achieve ligand-dependent and ligand-independent EGFR activation; IL-8 mRNA was measured by real-time PCR and IL-8 and MIP-1α protein measured by enzyme-linked immunosorbent assay (ELISA). Epithelial IL-8 and EGFR expression in bronchial biopsies from asthmatic subjects was examined by immunohistochemistry and quantified by image analysis.Results Using H292 cells, EGF and H2O2 increased IL-8 gene expression and release and this was completely suppressed by the EGFR-selective tyrosine kinase inhibitor, AG1478, but only partially by dexamethasone. MIP-1α release was not stimulated by EGF, whereas H2O2 caused a 1.8-fold increase and this was insensitive to AG1478. EGF also significantly stimulated IL-8 release from asthmatic or normal primary epithelial cell cultures established from bronchial brushings. In bronchial biopsies, epithelial IL-8, MIP-1α, EGFR and submucosal neutrophils were all significantly increased in severe compared to mild disease and there was a strong correlation between EGFR and IL-8 expression (r = 0.70, P 〈 0.001).Conclusions These results suggest that in severe asthma, epithelial damage has the potential to contribute to neutrophilic inflammation through enhanced production of IL-8 via EGFR- dependent mechanisms.
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford BSL : Blackwell Science Ltd
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The mediators released during the allergic inflammatory reaction induce the clinical symptoms of the allergic disease and although there have been numerous studies investigating mediator release in allergen challenge models of allergic rhinitis very few have extended this approach to the study of natural disease.〈section xml:id="abs1-2"〉〈title type="main"〉ObjectiveThe aim of this investigation was therefore to measure mast cell and eosinophil mediator levels and indices of vascular permeability in naturally occurring rhinitis.〈section xml:id="abs1-3"〉〈title type="main"〉MethodsThree groups of subjects were studied, normal non-rhinitics, seasonal allergic rhinitics in and out of the grass pollen season and perennial allergic rhinitics. Mediators were recovered using the technique of nasal lavage and the levels of tryptase, histamine, eosinophil cationic protein and albumin were determined. In addition, eosinophils were enumerated in nasal smears as an indices of underlying inflammation.〈section xml:id="abs1-4"〉〈title type="main"〉ResultsThe levels of tryptase, eosinophil cationic protein and albumin were significantly higher in the lavage recovered from the symptomatic seasonal allergic rhinitics than when asymptomatic (P = 0.05, P = 0.003, P = 0.009, respectively). These levels of eosinophil cationic protein and albumin were also significantly higher than those of the normal non-rhinitics (P = 0.0008, P = 0.0.003, respectively). In the perennial allergic rhinitics the levels of tryptase, eosinophil cationic protein and albumin were higher than the normal non-rhinitics (P  〈 0.0001, P = 0.0003, P = 0.0001, respectively). The levels of tryptase and histamine were higher in the perennial allergic rhinitics than the seasonal allergic rhinitics (P = 0.0003, P = 0.006, respectively). These changes in mediator levels were accompanied by a significant influx of eosinophils into the nasal mucosa of both the symptomatic seasonal rhinitics, compared with asymptomatic (P = 0.04) and normal controls (P = 0.0006) and the perennial rhinitics compared to normal controls (P = 0.03).〈section xml:id="abs1-5"〉〈title type="main"〉ConclusionThese results indicate that in both naturally occurring seasonal allergic rhinitis and perennial allergic rhinitis mast cell and eosinophil activation occurs and this is accompanied by an increase in vascular permeability. These measurements in lavage fluid provide a method of monitoring the mucosal cellular events in response to therapy.
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  • 6
    ISSN: 1432-2072
    Keywords: Key words Sleep ; Depression ; Antidepressant ; SSRIs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rationale: The effects of antidepressants on sleep in depression have been extensively investigated, although to date there have been relatively few studies of newer drug classes such as specific serotonin reuptake inhibitors (SSRIs). All reported studies on SSRIs have been conducted in patients admitted to sleep laboratories and very few longitudinal studies have continued to measure sleep beyond 5 weeks of treatment. The growing trend towards outpatient and community care has highlighted the need for studies of sleep in depression in a more naturalistic setting, and during longer periods of treatment in line with recommended clinical practice. Objectives: To establish if the changes in sleep architecture and continuity described during early treatment with SSRIs persist after 3 months, to relate these changes to clinical state, and to establish whether home recordings would yield similar results to previous laboratory studies. Methods: We have recorded objective sleep parameters in 12 depressed patients before and during 12-week treatment with an SSRI, fluvoxamine. All the sleep recordings were performed in the patients’ own homes, using the Oxford Medilog system. Results: At 12 weeks, 7/12 patients had responded (HAM-D decreased by 〉50%). REM latency showed the expected increase early in treatment; this change was less obvious at weeks 3 and 12. Amount of REM sleep was decreased at day 2 and week 3, but returned to baseline by week 12. Slow wave sleep was slightly increased at day 2 and decreased at week 12. Of the sleep continuity measures, the only significant change was in sleep onset latency, which was increased at week 3; the other measures showed non- significant worsening at night 2 and week 3, but most were better than baseline by 12 weeks. Subjective sleep (the three sleep items on the HAM-D) showed a progressive improvement over time, especially in the responders. Conclusions: The effects of the SSRI fluvoxamine on objective sleep measures are in the direction predicted by its pharmacological actions and some persist for at least 12 weeks. In addition subjective appraisal of sleep is strongly affected by mood state. All patients found the home recording procedure acceptable and only minimally disruptive.
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  • 7
    ISSN: 1573-0794
    Source: Springer Online Journal Archives 1860-2000
    Topics: Geosciences , Physics
    Notes: Abstract The generalized Eddington approximation, obtained by the three-stream division of the radiation field, is used to compute the intensity falling on the nucleus head of a spherically-symmetric comet illuminated by parallel solar radiation.
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  • 8
    ISSN: 1573-2657
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Summary The generation of myotubes was studied in the tibialis cranialis muscle in the sheep hindlimb from the earliest stage of primary myotube formation until a stage shortly before muscle fascicles began to segregate. Primary myotubes were first seen on embryonic day 32 (E32) and reached their maximum number by E38. Small numbers of secondary myotubes were first identified at E38, and secondary myotube numbers continued to increase during the period of study. The ratio of adult muscle fibre to primary myotube numbers was approximately 70∶1, making it seem unlikely that every later generation myotube used a primary myotube as scaffold for its formation, as described in small mammals. By E62, some secondary myotubes were supporting the formation of a third generation of myotubes. Experiments with diffusible dye markers showed that primary myotubes extended from tendon to tendon of the muscle, whereas most adult fibres ran for only part of the muscle length, terminating with myo-myonal attachments to other muscle fibres in a series arrangement. Acetylcholinesterase (AChE) and acetylcholine receptor (AChR) aggregations appeared in multiple bands across the muscle shortly after formation of the primary generation of myotubes was complete. The number of bands and their pattern of distribution across the muscle as they were first formed was the same as in the adult. Primary myotubes teased from early muscles had multiple focal AChE and AChR deposits regularly spaced along their lengths. We suggest that the secondary generation of myotubes forms at endplate sites in a series arrangement along the length of single primary myotubes, and that tertiary and possibly later generations of myotubes in their turn use the earlier generation myofibres as a scaffold. Although the fundamental cellular mechanisms appear to be similar, the process of muscle fibre generation in large mammalian muscles is more complex than that described from previous studies in small laboratory rodents.
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  • 9
    ISSN: 1573-2878
    Keywords: Parabolic differential equations ; first boundary-value problems ; optimal control problems with terminal inequality constraints ; algorithms ; relaxed controls ; convergence of algorithms
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract In this paper, we consider a class of optimal control problems with control and terminal inequality constraints, where the system dynamics is governed by a linear second-order parabolic partial differential equation with first boundary condition. A feasible direction algorithm for solving this class of optimal control problems has already been obtained in the literature. The aim of this paper is to improve the convergence result by using a topology arising in the study of relaxed controls.
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  • 10
    ISSN: 1573-2878
    Keywords: Nonlinear time-lag systems ; linear control constraints ; nonlinear terminal inequality constraints ; feasible direction methods ; accumulation points ; relaxed controls ; relaxed control problems ; necessary conditions for optimality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics
    Notes: Abstract In this paper, we consider a class of time-lag optimal control problems involving control and terminal inequality constraints. A feasible direction algorithm has been obtained by Teo, Wong, and Clements for solving this class of optimal control problems. It was shown that anyL ∞ accumulation points of the sequence of controls generated by the algorithm satisfy a necessary condition for optimality. However, suchL ∞ accumulation points need not exist. The aim of this paper is to prove a convergence result, which ensures that the sequence of controls generated by the algorithm always has accumulation points in the sense of control measure, and these accumulation points satisfy a necessary condition for optimality for the corresponding relaxed problem.
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