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  • 1
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    Journal of neurochemistry 82 (2002), S. 0 
    ISSN: 1471-4159
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The motor signs of Parkinson's disease have been partly attributed to an overinhibition of the external globus pallidus (GP) that results from hyperactivity of striatopallidal GABA/enkephalinergic neurons. The goals of this study were to measure basal levels of extracellular fluid GABA in the GP of normal cats, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian cats and cats spontaneously recovered from MPTP-induced parkinsonism, and to examine the effects of opioid receptor activation on potassium (K+)-evoked GABA release in the GP in these animals. Basal GP GABA levels were increased 75% from normal in parkinsonian animals 1 week after MPTP administration and returned to control levels in recovered animals 6 weeks afterMPTP administration. No significant differences were observed in K+-evoked GABA release across conditions. The opioid receptor agonist [D-Ala2]-Met-Enkephalinamide (DALA) significantly attenuated K+-evoked GABA release in the GP of MPTP-treated symptomatic and recovered cats, but had no significant effect on GABA release in normal animals. These data show that basal GP GABA levels are elevated coincident with expression of parkinsonian signs and return to normal in animals that have functionally compensated for a nigrostriatal lesion. DALA-induced inhibition of pallidal GABA release after a dopamine-depleting lesion, suggests that enkephalin may attenuate GABA release in the GP specifically after striatal dopamine loss.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    Clinical & experimental allergy 31 (2001), S. 0 
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background Desloratadine is a non-sedating, clinically effective, anti-allergic therapy that has been shown to exhibit anti-inflammatory properties that extend beyond its ability to antagonize histamine at H1-receptor sites. This latter effect has been shown in vitro to be both IgE-dependent and -independent.Objective In this study, we addressed the ability of desloratadine to inhibit the in vitro generation of interleukin (IL)-4 and IL-13 from human basophils while concurrently comparing its efficacy in preventing mediator release by these cells.Methods Basophil-enriched suspensions were treated with various concentrations of desloratadine for 15 min before stimulating with either anti-IgE antibody, calcium ionophore, IL-3 or phorbol ester. Histamine (fluorimetry), LTC4 (RIA) and IL-4 (ELISA) were all assayed using the same 4-h culture supernatants. IL-13 (ELISA) was measured in supernatants harvested after 20 h incubation. IL-4 mRNA expression (dilutional RT-PCR) was also examined.Results Desloratadine was found to be nearly six–seven times more potent in preventing the secretion of IL-4 and IL-13 induced by anti-IgE than it was at inhibiting the release of histamine and LTC4. These cytokines were equally inhibited by desloratadine following activation with ionomycin despite the lack of an effect on the histamine induced with ionomycin. Desloratadine had a lesser effect regarding inhibition of the IL-13 secreted in response to IL-3 and PMA. There was no evidence that desloratadine mediated its inhibitory effects by causing decreased cell viability. Finally, IL-4 mRNA accumulation was remarkably inhibited, by as much as 80%, following pretreatment with desloratadine.Conclusion While capable of inhibiting histamine and LTC4 release by human basophils, desloratadine is more effective at targeting the signals regulating IL-4 and IL-13 generation in these cells. This inhibitory effect on cytokine generation provides additional evidence that this antihistamine exerts anti-inflammatory properties.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1365-2222
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background The complex interactions between immune cells are partly mediated by different adhesion molecules, but little is known about their role in the systemic immunoinflammatory process following sensitization to food antigens in early infancy.Objective The aim of this study was to investigate the expression of intercellular adhesion molecule-1 (ICAM-1or CD54) and the α subunits of its ligands' lymphocyte function-associated antigen-1 (LFA-1) (αL subunit or CD11a) and Mac-1 (αM subunit or CD11b) on peripheral blood leucocytes in infants with cow's milk allergy (CMA) and in healthy controls.Methods Thirty-nine breastfed infants, aged from 0.6 to 8.3 months, and their lactating mothers were included in the study from delivery onwards. During follow-up, 25 infants developed CMA and 14 remained healthy. Expressions of CD54 and CD11b on peripheral blood leucocytes were evaluated by flow cytometry. In addition, the expression of CD11a on peripheral blood leucocytes was analysed by immunocytochemistry. Mothers' milk samples were collected and their leucocyte content was evaluated using a light microscope.Results The frequency of ICAM-1 expressing peripheral blood lymphocytes was significantly higher in patients with CMA than in healthy infants (P=0.03, Mann–Whitney U-test). Furthermore, the high proportion of ICAM-1-expressing cells was associated with gastrointestinal and multiorgan symptoms in the CMA infants. There was no significant difference in the expression of Mac-1 αM on lymphocytes in our study groups, but the LFA-1 αL expression seemed to be higher in the IgE-mediated CMA.Conclusion We suggest that the high expression of ICAM-1 on peripheral blood lymphocytes may reflect enhanced stimulation of T cells in vivo and their migration to the effector tissues in an early-phase of developing CMA. Furthermore, high ICAM-1 expression may be associated with the presence of multiorgan manifestations of CMA, whereas high LFA-1 expression may reflect the IgE-mediated disease.
    Type of Medium: Electronic Resource
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  • 4
    Publication Date: 2015-07-09
    Print ISSN: 1045-2249
    Electronic ISSN: 1465-7279
    Topics: Biology
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  • 5
    Publication Date: 2013-01-03
    Description: The spectra of several high-redshift ( z 〉 6) quasars have shown indications for a Gunn–Peterson (GP) damping wing, suggesting a substantial mean neutral hydrogen fraction ( $\bar{x}_{\rm H\,{\scriptscriptstyle I}}^{\rm IGM}\gtrsim 0.03$ ) in the z 6 intergalactic medium (IGM). However, previous analyses assumed that the IGM was uniformly ionized outside of the quasar’s H  ii region. Here we relax this assumption and model patchy reionization scenarios for a range of IGM and quasar parameters. Compared to uniform reionization, patchy reionization imprints a different average damping wing profile with an associated sightline-to-sightline scatter. We quantify the impact of these differences on the inferred $\bar{x}_{\rm H\,{\scriptscriptstyle I}}^{\rm IGM}$ , by fitting the spectra of three quasars: SDSS J1148+5251 ( z = 6.4189), J1030+0524 ( z = 6.308) and J1623+3112 ( z = 6.247). We find that the best-fitting values of $\bar{x}_{\rm H\,{\scriptscriptstyle I}}^{\rm IGM}$ in the patchy models agree well with the uniform case. More importantly, we confirm that the observed spectra favour the presence of a GP damping wing, with peak likelihoods decreasing by factors of few–10 when the spectra are modelled without a damping wing. We also find that the Lyα absorption spectra, by themselves, cannot distinguish the damping wing in a relatively neutral IGM from a damping wing in a highly ionized IGM, caused either by an isolated neutral patch or by a damped Lyα absorber (DLA). However, neutral patches in a highly ionized universe ( $\bar{x}_{\rm H\,{\scriptscriptstyle I}}^{\rm IGM}\lesssim 10^{-2}$ ) and DLAs with the large required column densities ( $N_{\rm H\,{\small I}}\gtrsim {\rm { few}}\times 10^{20}{\rm { cm}^{-2}}$ ) are both rare. As a result, when we include reasonable prior probabilities for the line of sight (LOS) to intercept either a neutral patch or a DLA at the required distance of ~ 40-60 comoving Mpc away from the quasar, we find strong lower limits on the neutral fraction in the IGM, $\bar{x}_{\rm H\,{\scriptscriptstyle I}}^{\rm IGM}\gtrsim 0.1$ (at 95 per cent confidence). This supports earlier claims that a substantial global fraction of hydrogen in the z 6 IGM is in neutral form.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 6
    Publication Date: 2012-09-06
    Description: Nonpigmented Yersinia pestis ( pgm ) strains are defective in scavenging host iron and have been used in live-attenuated vaccines to combat plague epidemics. Recently, a Y. pestis pgm strain was isolated from a researcher with hereditary hemochromatosis who died from laboratory-acquired plague. We used hemojuvelin-knockout ( Hjv –/– ) mice to examine whether iron-storage disease restores the virulence defects of nonpigmented Y. pestis . Unlike wild-type mice, Hjv –/– mice developed lethal plague when challenged with Y. pestis pgm strains. Immunization of Hjv –/– mice with a subunit vaccine that blocks Y. pestis type III secretion generated protection against plague. Thus, individuals with hereditary hemochromatosis may be protected with subunit vaccines but should not be exposed to live-attenuated plague vaccines.
    Print ISSN: 0022-1899
    Electronic ISSN: 1537-6613
    Topics: Medicine
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  • 7
    Publication Date: 2016-02-16
    Description: We employed a semi-Markov multistate model for the simultaneous analysis of various endpoints describing the course of breast cancer. Results were compared with those from standard analyses using a Cox proportional hazards model. We included 3,012 patients with invasive breast cancer newly diagnosed between 2001 and 2005 who were recruited in Germany for a population-based study, the Mamma Carcinoma Risk Factor Investigation (MARIE Study), and prospectively followed up until the end of 2009. Locoregional recurrence and distant metastasis were included as intermediate states, and deaths from breast cancer, secondary cancer, and other causes were included as competing absorbing states. Tumor characteristics were significantly associated with all breast cancer–related endpoints. Nodal involvement was significantly related to local recurrence but more strongly related to distant metastases. Smoking was significantly associated with mortality from second cancers and other causes, whereas menopausal hormone use was significantly associated with reduced distant metastasis and death from causes other than cancer. The presence of cardiovascular disease at diagnosis was solely associated with mortality from other causes. Compared with separate Cox models, multistate models allow for dissection of prognostic factors and intermediate events in the analysis of cause-specific mortality and can yield new insights into disease progression and associated pathways.
    Print ISSN: 0002-9262
    Electronic ISSN: 1476-6256
    Topics: Medicine
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  • 8
    Publication Date: 2012-08-15
    Description: Aims Dynamic three-dimensional-cardiac magnetic resonance (3D-CMR) perfusion proved highly diagnostic for the detection of angiographically defined coronary artery disease (CAD) and has been used to assess the efficacy of coronary stenting procedures. The present study aimed to relate significant coronary lesions as assessed by fractional flow reserve (FFR) to the volume of myocardial hypoenhancement on 3D-CMR adenosine stress perfusion imaging and to define the inter-study reproducibility of stress inducible 3D-CMR hypoperfusion. Methods and results A total of 120 patients with known or suspected CAD were examined in two CMR centres using 1.5 T systems. The protocol included cine imaging, 3D-CMR perfusion during adenosine infusion, and at rest followed by delayed enhancement (DE) imaging. Fractional flow reserve was recorded in epicardial coronary arteries and side branches with ≥2 mm luminal diameter and 〉40% severity stenosis (pathologic FFR 〈 0.75). Twenty-five patients underwent an identical repeat CMR examination for the determination of inter-study reproducibility of 3D-CMR perfusion deficits induced by adenosine. Three-dimensional CMR perfusion scans were visually classified as pathologic if one or more segments showed an inducible perfusion deficit in the absence of DE. Myocardial ischaemic burden (MIB) was measured by segmentation of the area of inducible hypoenhancement and normalized to left ventricular myocardial volume (MIB, %). Three-dimensional CMR perfusion resulted in a sensitivity, specificity, and diagnostic accuracy of 90, 82, and 87%, respectively. Substantial concordance was found for inter-study reproducibility [Lin's correlation coefficient: 0.98 (95% confidence interval: 0.96–0.99)]. Conclusion Three-dimensional CMR stress perfusion provided high diagnostic accuracy for the detection of functionally significant CAD. Myocardial ischaemic burden measurements were highly reproducible and allowed the assessment of CAD severity.
    Print ISSN: 0195-668X
    Electronic ISSN: 1522-9645
    Topics: Medicine
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  • 9
    Publication Date: 2014-04-29
    Description: Potassium (K + )-uptake transport proteins present in prokaryote and eukaryote cells are categorized into two classes; Trk/Ktr/HKT, K + channel, and Kdp belong to the same superfamily, whereas the remaining K + -uptake family, Kup/HAK/KT has no homology to the others, and neither its membrane topology nor crucial residues for K + uptake have been identified. We examined the topology of Kup from Escherichia coli . Results from the reporter fusion and cysteine labeling assays support a model with 12 membrane-spanning domains. A model for proton-coupled K + uptake mediated by Kup has been proposed. However, this study did not show any stimulation of Kup activity at low pH and any evidence of involvement of the three His in Kup-mediated K + uptake. Moreover, replacement of all four cysteines of Kup with serine did not abolish K + transport activity. To gain insight on crucial residues of Kup-mediated K + uptake activity, we focused on acidic residues in the predicted external and transmembrane regions, and identified four residues in the membrane regions required for K + uptake activity. This is different from no membrane-localized acidic residues essential for Trk/Ktr/HKTs, K + channels and Kdp. Taken together, these results demonstrate that Kup belongs to a distinct type of K + transport system.
    Print ISSN: 0021-924X
    Electronic ISSN: 1756-2651
    Topics: Biology , Chemistry and Pharmacology
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