bluuebunny/crossref_metadata_2025_split huggingface dataset:
Profiting from the Euro? Seigniorage Gains from Euro Area Accession
Authors: Gros Daniel 
Published: October 2004

AbstractThis article puts forward a methodology to assess the fiscal implications for the new EU members from central and eastern Europe (CEECs) of joining the euro area. An application of this methodology under a specific set of conditions shows that the rules of the ECB on the distribution of seigniorage favour poorer countries so that one would expect the new member countries to benefit from participating in the distribution of the profits of the ECB. For two countries the gains could indeed be sizeable, initially almost 1 per cent of GDP, per annum. But for others the gains are more modest. Two factors have tended to reduce the expected financial gains for the new Member States: firstly, since the introduction of the euro, cash use has fallen considerably in the euro area; and secondly, some of the new CEEC members have in general much higher cash‐to‐GDP ratios and therefore earn, for the time being, relatively high domestic seigniorage revenues. Illustrative calculations show that, in present value terms, the gains could reach up to 10 per cent of GDP for poorer countries that catch up only slowly to the EU average. But countries that enter with a GDP per capita above about one‐half of the EU average might actually lose if initially their cash ratios are much above the euro area value.
Risk‐sharing and EMU
Authors: Mélitz Jacques 
Published: October 2004

AbstractWhat are the prospects that risk‐sharing in EMU will ever attain the levels in the US? So far as risk‐sharing in the US depends on interregional transfers through the budget of the federal government, those prospects are poor. So far as the risk‐sharing in the US takes place though market channels, they are much better. This article addresses the theory and evidence on the subject. The evidence would indicate that EMU still lags far behind the US as regards the pooling of risks through portfolio diversification. But there already seems to be little to distinguish the euro area from the US in the ability to borrow to smooth shocks. Thus, some extra risk‐sharing should already be taking place in the euro area through this channel. But how much? Further, there is also evidence that the progress of European economic and monetary integration over the last decade has increased the symmetry of business cycles. But this evidence is difficult to interpret. It could even be a sign of remaining capital‐market imperfections. With respect to the theoretical aspects, one of the issues in the article is the adequacy of the general framework that Asdrubali, Sørensen and Yosha have proposed for dealing with all of these questions.
Repeated dosing with donepezil does not affect the safety, tolerability or pharmacokinetics of single‐dose thioridazine in young volunteers
Authors: Ravic Miroslav , Warrington Steve , Boyce Malcolm , Dunn Kate , Johnston Atholl 
Published: October 2004

AimTo investigate the effects of donepezil at steady state on the safety, tolerability and pharmacokinetics of a single dose of thioridazine, in healthy subjects.MethodsAn open, two‐way, balanced crossover study, in 12 subjects (six men and six women) aged 19–41 years. During both treatment periods, subjects received a single oral dose of 50 mg thioridazine; in one period the thioridazine was given alone, and in the other period it was given together with the last of 15 daily, oral doses of donepezil 5 mg. The ‘washout’ periods were 1 week when thioridazine was given first, and 2 weeks when thioridazine was given last. Plasma concentrations of thioridazine were measured after each dose, and pharmacokinetic parameters were determined. Interactions were tested by using an equivalence analysis in which thioridazine was the ‘Reference’ and thioridazine + donepezil the ‘Test’ regimen. Safety and tolerability were monitored.ResultsDonepezil had no marked effect on the pharmacokinetics of thioridazine, as judged by the equivalence analysis of AUC0–tn, AUC0–∞, t½ and tmax. Cmax was very similar in the ‘Test’ and ‘Reference’ regimens, but the confidence intervals were too wide to confirm equivalence. Donepezil was well tolerated, whereas thioridazine was associated with light‐headedness, tiredness and postural hypotension, irrespective of whether or not donepezil was given concurrently.ConclusionsRepeated dosing with donepezil, 5 mg daily for 2 weeks, had no significant effect on the safety, tolerability or pharmacokinetics of thioridazine. Thioridazine was poorly tolerated.
Concurrent administration of donepezil HCl and sertraline HCl in healthy volunteers: assessment of pharmacokinetic changes and safety following single and multiple oral doses
Authors: Nagy Christa F. , Kumar Dinesh , Perdomo Carlos A. , Wason Suman , Cullen Edward I. , Pratt Raymond D. 
Published: October 2004

AimThis study evaluated the safety and pharmacokinetics (PK) of donepezil HCl and sertraline HCl when administered separately and in combination.MethodsThis was a randomized, open‐label, three‐period crossover study. In consecutive dosing periods separated by washout periods of ≥ 3 weeks, healthy volunteers received either oral donepezil HCI 5 mg once daily for 15 days, oral sertraline HCl 50 mg once daily for 5 days followed by 10 days of once‐daily sertraline HCl 100 mg, or the simultaneous administration of oral donepezil HCl and sertraline HCl. Plasma donepezil and sertraline concentrations were determined by high performance liquid chromatography/mass spectrometry. Safety was evaluated by physical and laboratory evaluations and the monitoring of adverse events (AEs).ResultsA total of 19 volunteers (16 male and three female) were enrolled. Three male subjects withdrew from the study prematurely due to AEs (one case of nausea/stomach cramps and one case of eosinophilia during combination treatment, and one upper respiratory tract infection during treatment with sertraline HCl alone). In subjects who completed all three treatment periods (n = 16), the concurrent administration of donepezil HCl and sertraline HCl did not alter the steady‐state (day 15) PK parameters of donepezil HCl. A small (< 12%) but statistically significant (P = 0.02) increase in donepezil Cmax was seen after single doses of sertraline HCl and donepezil HCl on day 1 but this was not thought to be clinically meaningful. No significant differences in the tmax or AUC0−24 h of donepezil were observed between the donepezil HCl only or donepezil HCl plus sertraline HCl groups on day 1. No significant changes in sertraline PK parameters were observed either on day 1 (single dose) or on day 15 (steady state) when sertraline HCl was co‐administered with donepezil HCl. Generally, the concurrent administration of donepezil HCl and sertraline HCl was well tolerated, with no serious AEs reported during the study. Some digestive system AEs tended to occur more frequently during combination treatment than with either treatment alone, but there was no statistically significant increase in the incidence of any individual AE. The most common AEs during the combination therapy were nausea and diarrhoea, which were rated as mild or moderate in severity. These AEs were also reported during the administration of each drug alone.ConclusionsThe co‐administration of once‐daily oral donepezil HCl 5 mg for 15 days and once‐daily oral sertraline HCl (50 mg for 5 days increased to 100 mg for 10 days) did not result in any clinically meaningful pharmacokinetic interactions, and no unexpected AEs were observed.
The safety and tolerability of donepezil in patients with Alzheimer's disease
Authors: Jackson Stephen , Ham Richard J. , Wilkinson David 
Published: October 2004

Cholinesterase (ChE) inhibitors, which prevent the hydrolysis of acetylcholine, have been approved for the symptomatic treatment of Alzheimer's disease (AD) for over a decade. However, the first ChE inhibitors were associated with a high incidence of side‐effects and general tolerability concerns, including hepatotoxicity. Side‐effects associated with increased cholinergic activity, particularly in the gastrointestinal (GI) system, can prevent patients from achieving effective doses of drug. In addition, the advanced age and frail nature of patients with AD mean that poor tolerability is a serious concern. The potential for drug–drug interactions is also an important consideration, due to the high prevalence of comorbid disease in these patients.Data both from clinical trials and studies in routine clinical practice have shown that donepezil is associated with a low incidence of GI adverse events (AEs) that is comparable with placebo. Donepezil is a potent, selective inhibitor of acetylcholinesterase, and selective inhibition of central as opposed to peripheral ChEs might be expected to reduce the incidence of AEs, thus this may explain the lower incidence of cholinergic AEs observed following treatment with donepezil, compared with nonselective ChE inhibitors.There are no differences in cardiovascular AEs, including bradycardia, between placebo and donepezil groups in the clinical trials published to date, even in a very sick vascular dementia population with high rates of comorbidity and concomitant medication use.Data from single‐ and multiple‐dose studies of donepezil in patients with hepatic impairment and with moderately to severely impaired renal function indicate that donepezil is safe and well tolerated in these groups. Furthermore, both in vitro and clinical studies have shown that donepezil is not associated with drug–drug interactions.The incidence of weight loss is very similar between donepezil‐ and placebo‐treated patients. Although insomnia and other sleep disorders have been reported following administration of donepezil, lengthening the time period before increasing the dose of donepezil from 5 to 10 mg day−1 or switching to morning dosing can reduce these events to the levels of placebo‐treated patients.Over 770 million days of patient use and an extensive publication database demonstrate that donepezil has a good tolerability and safety profile.
Imbalance between interleukin-1 agonists and antagonists: relationship to severity of inflammatory bowel disease
Authors: LUDWICZEK O , VANNIER E , BORGGRAEFE I , KASER A , SIEGMUND B , DINARELLO C A , TILG H 
Published: October 2004

SUMMARYInterleukin (IL)-1 is a key mediator in the pathogenesis of inflammatory bowel disease (IBD). Naturally occurring IL-1 modulators include IL-1 receptor antagonist (IL-1Ra), IL-1 soluble receptor Type I (IL-1sRI), IL-1sRII and IL-1 receptor accessory protein (AcP). Systemic and mucosal levels of IL-1 soluble receptors remain unknown in IBD. Plasma or colonic tissues were obtained from 185 consecutive unselected patients with Crohn's disease (CD) or ulcerative colitis (UC) and from 52 control subjects. Plasma and colonic explant culture supernatants were assessed for IL-1α, IL-1β, IL-1Ra, IL-1sRI and IL-1sRII. Plasma IL-1Ra levels were higher in UC (+93%) than in healthy subjects. IL-1α and IL-1β were not detected. IL-1sRII levels were marginally lower in CD (−10%) and UC (−9%), whereas IL-1sRI levels were elevated in CD (+28%) only. Plasma IL-1sRI levels correlated positively (P &lt; 0·01) with Crohn's disease activity index (r = 0·53), C-reactive protein (r = 0·46) and α1-acid glycoprotein (r = 0·42). In colonic explant cultures, IL-1α and IL-1Ra levels were elevated in non-lesional (+233% and +185% respectively) and lesional CD (+353% and +1069%), lesional UC (+604% and +1138%), but not in non-lesional UC. IL-1β was elevated in lesional UC (+152%) and CD (+128%). In contrast, IL-1sRII levels were elevated in non-lesional CD (+65%), but remained unchanged in lesional CD, non-lesional and lesional UC. IL-1sRI levels did not differ between patient and control groups. These results indicate that (i) the proinflammatory moiety IL-1sRI is a systemic marker of inflammation and activity in CD and (ii) local shedding of the functional antagonist IL-1sRII may dampen colonic inflammation in CD, but not in UC.
Antioxidant supplementation and nasal inflammatory responses among young asthmatics exposed to high levels of ozone
Authors: SIENRA-MONGE J J , RAMIREZ-AGUILAR M , MORENO-MACIAS H , REYES-RUIZ N I , DEL RÍO-NAVARRO B E , RUIZ-NAVARRO M X , HATCH G , CRISSMAN K , SLADE R , DEVLIN R B , ROMIEU I 
Published: October 2004

SUMMARY
The inflammatory response to ozone in atopic asthma suggests that soluble mediators of inflammation are released in response to oxidant stress. Antioxidants may alleviate additional oxidative stress associated with photochemical oxidant pollution. This study investigates the impact of antioxidant supplementation on the nasal inflammatory response to ozone exposure in atopic asthmatic children. We conducted a randomized trial using a double-blinded design. Children with asthma (n = 117), residents of Mexico City, were given randomly a daily supplement of vitamins (50 mg/day of vitamin E and 250 mg/day of vitamin C) or placebo. Nasal lavages were performed three times during the 4-month follow-up and analysed for content of interleukin-6 (IL-6), IL-8, uric acid and glutathione (GSx). IL-6 levels in the nasal lavage were increased significantly in the placebo group after ozone exposure while no increase was observed in the supplement group. The difference in response to ozone exposure between the two groups was significant (P = 0·02). Results were similar for IL-8, but with no significant difference between the groups (P = 0·12). GSx decreased significantly in both groups. Uric acid decreased slightly in the placebo group. Our data suggest that vitamin C and E supplementation above the minimum dietary requirement in asthmatic children with a low intake of vitamin E might provide some protection against the nasal acute inflammatory response to ozone.
The − 564 A/G polymorphism in the promoter region of the proteinase 3 gene associated with Wegener's granulomatosis does not increase the promoter activity
Authors: PIETERS K , PETTERSSON Å , GULLBERG U , HELLMARK T 
Published: October 2004

SUMMARYProteinase 3 is the major autoantigen in patients with Wegener's granulomatosis. Earlier studies have shown that circulating leucocytes from patients with Wegener's granulomatosis show elevated proteinase 3 surface expression and mRNA levels. Wegener's granulomatosis patients also have increased levels of proteinase 3 in plasma. A single nucleotide polymorphism (SNP) (− 564 A/G SNP) in the promoter region has been associated with disease. This SNP introduces a new potential Sp1 transcription factor binding site that may be responsible for the observed up-regulated expression of proteinase 3. To investigate this a 740 base pair long region of the promoter was cloned from genomic DNA. The disease-associated − 564 A/G, as well as a control − 621 A/G exchange, were introduced by polymerase chain reaction mutagenesis and cloned into a luciferase reporter vector. Endogenous expression levels of proteinase 3 mRNA and promoter activity of the cloned constructs were measured in three myeloid cell lines, HL-60, U937 and NB-4, and in epithelial HeLa cells. The results demonstrate a good correlation between the endogenous proteinase 3 mRNA expression and the promoter activity, as judged by luciferase activity. However, no significant differences in activity between the wild-type, polymorphic and the mutated control variant were found. In conclusion, the − 564 A/G polymorphism is not responsible for the increased expression levels seen in myeloid cells from patients with Wegener's granulomatosis.
Multiplicity of the antibody response to GAD65 in Type I diabetes
Authors: GILLIAM L K , BINDER K A , BANGA J P , MADEC A-M , ORTQVIST E , KOCKUM I , LUO D , HAMPE C S 
Published: October 2004

SUMMARYType I diabetes (TID) is an autoimmune disease characterized in part by the presence of autoantibodies directed against glutamic acid decarboxylase 65 (GAD65), among other pancreatic islet antigens. We investigated the independent epitope specificities of these GAD65 antibodies (GAD65Ab) and their combinations in the sera of new onset TID patients and first-degree relatives positive for GAD65Ab. For our analysis, we used four GAD65-specific recombinant Fabs (rFabs) that recognize different conformational determinants of GAD65 located throughout the molecule, including the N-terminal, the middle and the C-terminal regions. We used these epitope-specific rFabs in competition assays to determine the binding specificity of the autoantibodies found in patient sera. Among the 61 sera from newly diagnosed GAD65Ab-positive TID patients GAD65 binding was competed for 23 sera by all four rFabs, 29 by at least two rFabs, and in nine sera were displaced by one or no rFab. In contrast, none of the 24 sera from GAD65Ab-positive first-degree relatives of TID patients were displaced by all four rFabs. When using all four rFabs simultaneously to compete with GAD65Ab binding, binding of sera from TID patients was reduced by an average of 70%. A significantly weaker competition was observed when evaluating sera of GAD65Ab-positive first-degree relatives (P &lt; 0·0001).
The role of pneumolysin in pneumococcal pneumonia and meningitis
Authors: HIRST R A , KADIOGLU A , O'CALLAGHAN C , ANDREW P W 
Published: October 2004

SUMMARYDiseases caused by Streptococcus pneumoniae include pneumonia, septicaemia and meningitis. All these are associated with high morbidity and mortality. The pneumococcus can colonize the nasopharynx, and this can be a prelude to bronchopneumonia and invasion of the vasculature space. Proliferation in the blood can result in a breach of the blood–brain barrier and entry into the cerebrospinal fluid (CSF) where the bacteria cause inflammation of the meningeal membranes resulting in meningitis. The infected host may develop septicaemia and/or meningitis secondary to bronchopneumonia. Also septicaemia is a common precursor of meningitis. The mechanisms surrounding the sequence of infection are unknown, but will be dependent on the properties of both the host and bacterium. Treatment of these diseases with antibiotics leads to clearance of the bacteria from the infected tissues, but the bacteriolytic nature of antibiotics leads to an acute release of bacterial toxins and thus after antibiotic therapy the patients can be left with organ-specific deficits. One of the main toxins released from pneumococci is the membrane pore forming toxin pneumolysin. Here we review the extensive studies on the role of pneumolysin in the pathogenesis of pneumococcal diseases.
Cytokine mRNA repertoire of peripheral blood mononuclear cells in Takayasu's arteritis
Authors: Tripathy N Kumar , Chauhan S Kumar , Nityanand S 
Published: October 2004

SUMMARYWe have investigated constitutive and phytohaemagglutinin (PHA) + phorbol 12-myristate 13-acetate (PMA)-induced gene expression of tumour necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, IL-3, IL-4, IL-10, IL-12 and granulocyte macrophage colony-stimulating factor (GM-CSF) in peripheral blood mononuclear cells (PBMCs) of 10 patients with Takayasu's arteritis (TA) and 10 healthy controls by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). The constitutive mRNA expression of TNF-α (69·0 ± 4·0%versus 27·5 ± 18·0%; P = 0·001) and IL-4 (60·0 ± 10·0%versus 0%; P = 0·001) was significantly higher in patients than controls; that of IL-3 was comparable in both groups (38·0 ± 6·0%versus 32·0 ± 5·0%; P = 0·651) while no constitutive mRNA expression was observed for the other cytokines studied. The stimulated PBMCs of patients, as compared with the controls, had higher mRNA gene expression of TNF-α (127·0 ± 16·0%versus 54·0 ± 6·0%; P = 0·001), IFN-γ (93·0 ± 13·0%versus 57·0 ± 5·0%; P = 0·032), IL-2 (109·0 ± 13·0%versus 68·0 ± 6·0%; P = 0·015), IL-3 (60·0 ± 8·0%versus 21·2 ± 3·0%; P = 0·045) and IL-4 (68·0 ± 7·0%versus 27·0 ± 7·2%; P = 0·01) The mRNA expression of IL-10 was lower in patients than controls (35·0 ± 8·0%versus 75·0 ± 12·0%; P = 0·022). The GM-CSF mRNA was similar (102·0 ± 6·0%versus 89·0 ± 5·0%; P = 0·475) in both groups. Stimulation of cells with PHA + PMA showed no IL-12 expression but stimulation with lipopolysaccharide induced higher IL-12 mRNA in patients than controls (83·0 ± 14·0%versus 33·0 ± 4·0%; P = 0·005). Our data suggest that an inflammatory cytokine signature exists in TA with a key role for TNF-α, IL-4, IL-10 and IL-12 in different pathological processes of the disease.
Interleukin-12 up-regulates perforin- and Fas-mediated lymphokine-activated killer activity by intestinal intraepithelial lymphocytes
Authors: EBERT E C 
Published: October 2004

SUMMARYHuman intraepithelial lymphocytes (IELs) comprise a unique compartment of memory T cell receptor (TCR)-αβ +CD8+ T lymphocytes interspersed between intestinal epithelial cells. They develop potent lymphokine-activated killer (LAK) activity with interleukin (IL)-15, a cytokine that is found in excess in certain mucosal inflammatory states. IL-12, released by activated antigen-presenting cells, is known to potentiate perforin-induced cytotoxicity. This study evaluates the mechanism by which IL-12 up-regulates LAK activity. When IELs were stimulated with IL-15, the CD94+ IEL subset expanded and carried out cytotoxic activity in redirected lysis against P815 cells as well as Fas ligand (FL)- and tumour necrosis factor (TNF)-α-mediated lysis of Jurkat and WEHI cells, respectively. IL-12 enhanced the perforin- and FL-, but not TNF-α-mediated events. In addition, the up-regulated killing of HT-29 cells by IL-12 was reduced by concanamycin (which targets perforin) and antibody neutralizing FL but not by anti-TNF-α antibody. Furthermore, IL-12 augmented IL-15-stimulated release of serine esterases as well as expression of perforin and FL by IELs, but not TNF-α. This study shows that LAK activity, carried out by the CD94+ IELs, involves perforin, FL and TNF-α. IL-12 up-regulates the first two mechanisms of action, showing for the first time its effect on FL production and lytic activity.
The lung cytokine microenvironment influences molecular events in the lymph nodes during Th1 and Th2 respiratory mucosal sensitization to antigenin vivo
Authors: RITZ S A , CUNDALL M J , GAJEWSKA B U , SWIRSKI F K , WILEY R E , ALVAREZ D , COYLE A J , STAMPFLI M R , JORDANA M 
Published: October 2004

SUMMARYOriginally defined by their patterns of cytokine production, Th1 and Th2 cells have been described more recently to express other genes differentially as well, at least in vitro. In this study we compared the expression of Th1- and Th2-associated genes directly during in vivo sensitization to ovalbumin (OVA) in Th1- and Th2-polarized models of airways inflammation. Th1-polarized airway inflammation was achieved by the intranasal instillation of adenoviral vectors (Ad) encoding granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-12, followed by daily aerosolizations of OVA; instillation of Ad/GM-CSF alone with OVA aerosolization led to Th2-polarized responses. Lymph nodes were obtained at various time-points, RNA extracted, and analysed by real-time quantitative polymerase chain reaction (PCR). Consistent with reports from in vitro and human studies, mice undergoing Th1-polarized inflammation showed preferential expression of the transcription factor t-bet, the chemokines IFN-γ inducible protein (IP)-10 and macrophage inflammatory protein 1 alpha (MIP-1-alpha), and the chemokine receptor CCR5. In contrast, the transcription factor GATA-3, the chemokines I-309 and thymus and activation regulated chemokine (TARC), and the chemokine receptors CCR3 and CCR4 were preferentially expressed in the Th2 model. Importantly, we also show that Ad/transgene expression remains compartmentalized to the lung after intranasal instillation. Flow cytometric analysis of lung myeloid dendritic cells indicated that B7.1 was expressed more strongly in the Th1 model than in the Th2 model. These studies provide a direct comparison of gene expression in in vivo Th1- and Th2-polarized models, and demonstrate that molecular events in the lymph nodes can be altered fundamentally by cytokine expression at distant mucosal sites.