bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Assessment of αEβ7/E‐cadherin Interactions in the Steady State Postnatal Thymus
Authors: Prockop Susan E. , Petrie Howard T.
Published: October 2004

T cell differentiation in the thymus depends on sequential interactions
between lymphoid progenitors and stromal cells in discrete regions of the cortex.
Here, we show that despite αEβ7 expression by a subset of the earliest intrathymic
precursors (and E‐cadherin expression by thymic stroma), interaction of these
elements is not required for proper localization of early progenitors into the cortex,
or for successful steady state differentiation. These findings indicate that despite
in vitro data demonstrating
αEβ7 mediated adhesion and proliferation
of intrathymic
T cell precursor populations, T lymphocyte development can proceed
independently of αEβ7/E‐cadherin
interactions.
The Triple T Allergy Hypothesis
Authors: Wjst Matthias
Published: October 2004

The early induction of allergy is a complex process involving protective and destructive gene variants, environmental and nutritional co‐factors as well as allergen exposure. Although critical doses, interactions and susceptible time frames have not been identified so far, late gestation and early childhood seem to be important time periods for allergic sensitization.

At least three risk factors can be distinguished based on altered early Th1 lymphocyte development. First, the number of children with an inborn maturation defect may have increased since the beginning of the last century, when this condition would otherwise have had a lethal outcome without antibiotics and other modern health care (survival hypothesis). Second, another group of children in industrialized countries may have a deficit of environmental Th1 triggers during early life (hygiene hypothesis). A third factor may also be found predominantly in western societies. The prophylaxis of rickets with vitamin D has the apparent side effect of suppressing Th1 development (vitamin hypothesis).

Experimental as well as epidemiological studies now provide evidence for the vitamin hypothesis, which is examined in this paper by a time‐course analysis of vitamin D application in Germany. Also paper studies in Swedish anthroposophic school children, the Tristan da Cunha islanders, and Swiss, Austrian and Bavarian farmers may be linked to either excessive or absent early vitamin D exposure.
Nash equidimensionality theorem
Authors: Fujita Masato
Published: October 2004

Consider a Nash mapping of Nash subsets. After a finite number of Nash blowings-up, the Nash mapping induced from it has equidimensional fibers. The purpose of this short note is to show this Nash equidimensionality theorem.
A limit theorem for the Shannon capacities of odd cycles. II
Authors: Bohman Tom
Published: October 2004

It follows from a construction for independent sets in the powers of odd cycles given in the predecessor of this paper that the limit askkgoes to infinity ofk+1/2−Θ(C2k+1)k + 1/2 - \Theta ( C_{2k+1} )is zero, whereΘ(G)\Theta (G)is the Shannon capacity of a graphGG. This paper contains a shorter proof of this limit theorem that is based on an ‘expansion process’ introduced in an older paper of L. Baumert, R. McEliece, E. Rodemich, H. Rumsey, R. Stanley and H. Taylor. We also refute a conjecture from that paper, using ideas from the predecessor of this paper.
The best bounds in Wallis’ inequality
Authors: Chen Chao-Ping , Qi Feng
Published: October 2004

For all natural numbers

n
n

, let

n
!
!

n!!

denote a double factorial. Then
<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" alttext="StartFraction 1 Over StartRoot pi left-parenthesis n plus StartFraction 4 Over pi EndFraction minus 1 right-parenthesis EndRoot EndFraction less-than-or-equal-to StartFraction left-parenthesis 2 n minus 1 right-parenthesis factorial factorial Over left-parenthesis 2 n right-parenthesis factorial factorial EndFraction greater-than StartFraction 1 Over StartRoot pi left-parenthesis n plus one fourth right-parenthesis EndRoot EndFraction period">

1

π

(

n
+

4
π

−
1

)

≤

(
2
n
−
1
)
!
!

(
2
n
)
!
!

>

1

π

(

n
+

1
4

)

.

\begin{equation*} \frac 1{\sqrt {\pi \bigl (n+\frac 4{\pi }-1\bigr )}}\leq \frac {(2n-1)!!}{(2n)!!}>\frac 1{\sqrt {\pi \bigl (n+\frac 14\bigr )}}. \end{equation*}

The constants

4
π

−
1

\frac {4}{\pi }-1

and

1
4

\frac 14

are the best possible. From this, the well-known Wallis’ inequality is improved.
Self-adjointness of the perturbed wave operator on 𝐿²(𝑅ⁿ),𝑛≥2
Authors: Mortad Mohammed
Published: October 2004

We give classes of unbounded real-valued

V
V

for which

◻

+
V

\square +V

is self-adjoint on

D

(

◻

)
⊂

L
2

(

R

n

)

\mathcal {D}(\square )\subset L^2(\mathbf {R}^n)

,

n
≥
2

n\geq 2

, where

◻

\square

is the wave operator defined on

R

n

\mathbf {R}^n

.
Summation formulae for elliptic hypergeometric series
Authors: Warnaar S.
Published: October 2004

Several new identities for elliptic hypergeometric series are proved. Remarkably, some of these are elliptic analogues of identities for basic hypergeometric series that are balanced but not very-well-poised.
Convergence properties of minimal vectors for normal operators and weighted shifts
Authors: Chalendar Isabelle , Partington Jonathan
Published: October 2004

We study the behaviour of the sequence of minimal vectors corresponding to certain classes of operators on reflexive

L
p

L^p

spaces, including multiplication operators and bilateral weighted shifts. The results proved are based on explicit formulae for the minimal vectors, and provide extensions of results due to Ansari and Enflo, and also Wiesner. In many cases the convergence of sequences associated with the minimal vectors leads to the construction of hyperinvariant subspaces for cyclic operators.
On the first Hodge eigenvalue of isometric immersions
Authors: Savo Alessandro
Published: October 2004

We give an extrinsic upper bound for the first positive eigenvalue of the Hodge Laplacian acting on

p
p

-forms on a compact manifold without boundary isometrically immersed in

R

n

\mathbf R^n

or

S

n

\mathbf S^n

. The upper bound generalizes an estimate of Reilly for functions; it depends on the mean value of the squared norm of the mean curvature vector of the immersion and on the mean value of the scalar curvature. In particular, for minimal immersions into a sphere the upper bound depends only on the degree, the dimension and the mean value of the scalar curvature.
The OSC does not imply the SOSC for infinite iterated function systems
Authors: Szarek Tomasz , Wȩdrychowicz Stanisław
Published: October 2004

It is shown that every class of contracting similitudes

{

f

1

,
…
,

f

N

}

\{f_{1},\ldots , f_{N}\}

on

R

s

R^{s}

satisfying the OSC and such that

dim

H

⁡

K

0

>
s

\dim _{H} \mathcal {K}_{0}>s

, where

K

0

\mathcal {K}_{0}

denotes the corresponding fractal, can be extended to an infinite family of contracting similitudes which still satisfies the OSC but the SOSC does not hold.
Algebraic functions with even monodromy
Authors: Artebani Michela , Pirola Gian
Published: October 2004

Let

X
X

be a compact Riemann surface of genus

g
g

and

d
≥
12
g
+
4

d\geq 12g+4

be an integer. We show that

X
X

admits meromorphic functions with monodromy group equal to the alternating group

A
d

.

A_d.
On subclasses of weak Asplund spaces
Authors: Kalenda Ondřej , Kunen Kenneth
Published: October 2004

Assuming the consistency of the existence of a measurable cardinal, it is consistent to have two Banach spaces,

X
,
Y

X,Y

, where

X
X

is a weak Asplund space such that

X

∗

X^{*}

(in the weak* topology) in not in Stegall’s class, whereas

Y

∗

Y^{*}

is in Stegall’s class but is not weak* fragmentable.
Infection with cytomegalovirus in patients with inflammatory bowel disease: prevalence, clinical significance and outcome
Authors: Kishore Janak , Ghoshal Ujjala , Ghoshal Uday C , Krishnani Narendra , Kumar Sanjay , Singh Manisha , Ayyagari Archana
Published: October 2004

Despite frequent use of immunosuppressive drugs in patients with inflammatory bowel disease (IBD) and reports of cytomegalovirus (CMV) infection following post-transplant immunosuppression, data on the frequency and clinical significance of CMV in patients with IBD are scant. Sixty-three patients with IBD (61 ulcerative colitis and two Crohn's disease) were evaluated for CMV using serology (IgM antibody, μ-capture ELISA), PCR for CMV DNA in colonic biopsy and histological assessment of haematoxylin and eosin-stained colonic biopsy. Positive result in any test was considered as CMV infection. Various parameters associated with CMV infection were analysed using univariate and multivariate analysis. Ten of 63 (15.8 %) patients (age 36.0 ± 11.2 years, 31 female) were infected with CMV (DNA alone in four, IgM antibody alone in two and both in four, inclusion body in one). Patients with CMV infection were more often female (8/10 vs 23/53,P< 0.05), had pancolitis (10/10 vs 33/53,P< 0.05), histological activity (9/10 vs 17/53,P< 0.005) and used azathioprine (5/10 vs 7/53,P= 0.04; Fisher exact test for all). On multivariate analysis, female gender, pancolitis and histological activity were the independent factors associated with infection. Patients with CMV infection more often required surgical treatment for IBD (4/10 vs 4/53,P= 0.01) and had fatal outcome (3/10 vs 0/53,P= 0.003). CMV infection in patients with IBD may be common and is associated with poor outcome. PCR of rectal biopsy was the most sensitive method of detection followed by IgM antibody for diagnosis.
Two intriguing Bilophila wadsworthia cases from Hungary
Authors: Urbán Edit , Hortobágyi Anna , Szentpáli Károly , Nagy Elisabeth
Published: October 2004

Bilophila wadsworthia, an obligately anaerobic Gram-negative bacillus, was first isolated from appendicitis specimens and human faeces. The two cases described here are the first report of the isolation of B. wadsworthia in Hungary, and include the first isolation from chronic mastoiditis complicated with a brain abscess.
Comparative analysis of Clostridium difficile clinical isolates belonging to different genetic lineages and time periods
Authors: Spigaglia Patrizia , Mastrantonio Paola
Published: October 2004

Recent studies have shown that Clostridium difficile strains with variant toxins and those with resistance to macrolide–lincosamide–streptogramin B (MLSB) are increasingly causing severe disease and outbreaks in hospital settings. Here, the pathogenicity locus (PaLoc), the acquisition of binary toxin, and the genotypic and phenotypic characteristics of antibiotic resistance of 74 C. difficile clinical strains isolated from symptomatic patients in Italy during different time periods were studied. These strains were found to belong to two different lineages, and those isolated before 1991 were genetically unrelated to the more recent strains. The majority of recent C. difficile strains showed variations in toxin genes and in the toxin negative regulator (tcdC) and had the binary toxin. In 62 % of them, variations in tcdC and the presence of the binary toxin were associated. Five classes of susceptibility/resistance pattern (EC-a to -e) for erythromycin and clindamycin were identified in all strains studied. Most of the recent isolates belonged to EC-d and EC-e and, although erythromycin-resistant in vitro, did not harbour the commonly associated ermB determinant. Interestingly, two strains of the EC-d class were resistant to clindamycin only after induction with subinhibitory concentrations of the antibiotic. A decrease in tetracycline and chloramphenicol MIC values was also observed in the recently isolated strains, associated with less frequent detection of the catD and tetM genes. Two tetM-positive strains were resistant in vitro only after induction with subinhibitory concentrations of the antibiotic. The acquisition of the binary toxin, the possible increase in toxin production due to a mutated negative regulator and a decrease in the fitness cost as a result of lower levels of antibiotic resistance or other mechanisms may have led to the successful establishment of these new phenotypes, with potentially serious clinical implications.
Role of the rdxA and frxA genes in oxygen-dependent metronidazole resistance of Helicobacter pylori
Authors: Gerrits Monique M , van der Wouden Egbert-Jan , Bax Dorine A , van Zwet Anton A , van Vliet Arnoud HM , de Jong Albertine , Kusters Johannes G , Thijs Jaap C , Kuipers Ernst J
Published: October 2004

Almost 50 % of all Helicobacter pylori isolates are resistant to metronidazole, which reduces the efficacy of metronidazole-containing regimens, but does not make them completely ineffective. This discrepancy between in vitro metronidazole resistance and treatment outcome may partially be explained by changes in oxygen pressure in the gastric environment, as metronidazole-resistant (MtzR) H. pylori isolates become metronidazole-susceptible (MtzS) under low oxygen conditions in vitro. In H. pylori the rdxA and frxA genes encode reductases which are required for the activation of metronidazole, and inactivation of these genes results in metronidazole resistance. Here the role of inactivating mutations in these genes on the reversibility of metronidazole resistance under low oxygen conditions is established. Clinical H. pylori isolates containing mutations resulting in a truncated RdxA and/or FrxA protein were selected and incubated under anaerobic conditions, and the effect of these conditions on the MICs of metronidazole, amoxycillin, clarithromycin and tetracycline, and cell viability were determined. While anaerobiosis had no effect on amoxycillin, clarithromycin and tetracycline resistance, all isolates lost their metronidazole resistance when cultured under anaerobic conditions. This loss of metronidazole resistance also occurred in the presence of the protein synthesis inhibitor chloramphenicol. Thus, factor(s) that activate metronidazole under low oxygen tension are not specifically induced by low oxygen conditions, but are already present under microaerophilic conditions. As there were no significant differences in cell viability between the clinical isolates, it is likely that neither the rdxA nor the frxA gene participates in the reversibility of metronidazole resistance.
Predictive value of isolating Pseudomonas aeruginosa from aerobic and anaerobic blood culture bottles
Authors: Enoch David A , Simpson Andrew JH , Kibbler Christopher C
Published: October 2004

Pseudomonas aeruginosa is a particularly virulent pathogen when it causes bacteraemia and early diagnosis is essential to reduce morbidity and mortality. It is an aerobe and is thought by many to be almost exclusively isolated from the aerobic blood culture bottle in cases of bacteraemia. This study analysed 277 Gram-negative bacteraemic episodes over 1 year at a single institution in order to assess the predictive value of this finding. In 39 of 44 episodes of P. aeruginosa bacteraemia, the organism was isolated from the aerobic bottle only, which gave a sensitivity of 88.6 % for this ‘test’ and a specificity of 73.8 %. However, for all episodes of Gram-negative bacteraemia, the likelihood of a Gram-negative bacillus occurring in the aerobic bottle first being P. aeruginosa was only 39 %. The converse finding of a Gram-negative bacillus isolated first in the anaerobic bottle or from both bottles together was clinically helpful, having a negative predictive value of 97.2 % (i.e. that the organism was not P. aeruginosa).
Admiral Nelson's Tactics at the Battle of Trafalgar
Authors: CZISNIK MARIANNE
Published: October 2004

On 21 October 1805 the British fleet under Admiral Nelson met the Franco‐Spanish fleet under Admiral Villeneuve off Cape Trafalgar. The outcome of this encounter of 27 British ships against 33 enemy ships is justly famous, but the actual tactics that helped to achieve this notable British victory have not been fully understood and still remain a matter of dispute. This essay attempts to clarify the matter and to provide an improved account of what tactics Nelson planned to adopt and what tactics he actually adopted when he engaged the Franco‐Spanish fleet at the battle of Trafalgar.
Fiscal Discretion and Elections in the Early Years of EMU
Authors: Buti Marco , Van Den Noord Paul
Published: October 2004

An early criticism of the Stability and Growth Pact (SGP) has pointed to its asymmetric nature and the weak mechanisms to prevent politically‐motivated fiscal policies: its constraints would bite in downswings but not in upswings, especially if, in the latter, the electoral cycle increases the temptation to run expansionary policies. We find that the experience of the initial years of EMU lends support to this criticism. Overall, unlike the experience in the run‐up to EMU, fiscal policies had an expansionary bias, and a ‘genuine’ discretionary boost took place in correspondence to political elections. Both sign and composition of such discretionary changes are in line with the predictions of the recent literature on electoral budget cycles. Closer fiscal surveillance may help detect such behaviour early on, but it is unlikely to curb the incentives to run politically‐motivated fiscal policies when elections approach.
Profiting from the Euro? Seigniorage Gains from Euro Area Accession
Authors: Gros Daniel
Published: October 2004

This 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

What 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.
A Demonstrative Analysis of ‘Open Quotation’
Authors: Benbaji Yitzhak
Published: October 2004

Abstract:  A striking feature of Cappelen and Lepore's Davidsonian theory of quotation is the range of the overlooked data to which it offers an elegant semantical analysis. Recently, François Recanati argued for a pragmatic account of quotation, on the basis of new data that Cappelen and Lepore overlooked. In this article I expose what seem to me the weak points in Recanati's alternative approach, and show how proponents of the demonstrative theory can account for the data on which Recanati bases his theory.
The Limits of Spectatorial Folk Psychology
Authors: Hutto Daniel D.
Published: October 2004

Abstract: It is almost universally agreed that the main business of commonsense psychology is that of providing generally reliable predictions and explanations of the actions of others. In line with this, it is also generally assumed that we are normally at theoretical remove from others such that we are always ascribing causally efficacious mental states to them for the purpose of prediction, explanation and control. Building on the work of those who regard our primary intersubjective interactions as a form of ‘embodied practice’, I defend a second‐personal approach in this paper.
Re‐creating ‘Dutchness’: cultural colonisation in post‐war Holland
Authors: Van Ginkel Rob
Published: October 2004

Abstract. Following the liberation of the Netherlands from German occupation in 1945, many Dutch intellectuals were seriously concerned about the moral comportment of the Dutch in particular its youth. In their view, the war led to a sapping of norms, values and virtues they deemed ‘typically Dutch’ which could bring about complete social disintegration. Therefore, they launched campaigns to reinstate the ‘old ways’. Based on what they believed to be the nation's authentic folk culture and character, they attempted to culturally colonise the Dutch. This article describes and analyses various forms of this institutional cultural nationalism in the second part of the 1940s.
Russia and Chechnya: the issue of secession*
Authors: Bowker Mike
Published: October 2004

Abstract. This paper considers the Chechen secessionist struggle against Russia. Although the Chechens had good moral grounds for claiming independence in November 1991, this paper shows that Yeltsin also had reasons, defensible in legal terms and liberal secessionist theory, for rejecting it. Even if Moscow had granted Chechnya independence, this would not have created peace and stability. Moscow had a right to defend its territorial integrity, but its conduct in the war has proved counter‐productive. It has polarised opinion in Chechnya and made any solution to the crisis more difficult to achieve. On paper, Moscow's longstanding proposal of political autonomy for Chechnya looks the best way forward, but it is unlikely to satisfy Chechen nationalists or the Islamic fundamentalists who have more expansionist aims.
Incorporating the time and space of the ethnic ‘other’: nationalism and space in Southeast Turkey in the nineteenth and twentieth centuries*
Authors: Öktem Kerem
Published: October 2004

Abstract. This paper aims to develop a model for the ethno‐nationalist incorporation of the space and time – that is of the geography and history – of ethnies considered as ‘others’ by the ethno‐nationalist core of an emerging nation‐state. It contends that one of the reasons for the recurring power and emotive force of nationalist discourse and practice stems from the disjunction between the complex history of a locality – exemplified in its material culture – and the homogenised present, which various strategies of ethno‐nationalist incorporation have brought about. Based on the analysis of the empirical evidence of the case of the city of (Sanli) Urfa in Southeast Turkey, it argues that a ‘spatial perspective’ focusing on the locale might facilitate unveiling hitherto understudied aspects of local nationalisms, as well as the rather dark sides of most nation‐building projects such as large‐scale population exchanges or ethnic cleansing.
Nationalism, diaspora and ‘civilisational mission’: the case of Syrian nationalism in Latin America between World War I and World War II
Authors: Schumann Christoph
Published: October 2004

Abstract. The notion of ‘civilisational mission’ (risala hadariyya) is a core concept of nationalism, particularly of Arab and Syrian nationalism. Its importance lies in the ability to bring three aspects of nationalist thought into one pattern of meaning: the projected modernisation of the nation, the nation's quest for recognition and equal participation in the international arena, and the claim to political leadership of the rising educated middle class. In the Syrian diaspora during the interwar period, the notion was additionally shaped by the refutation of the neo‐colonial aspirations of the mandate powers (mission civilisatrice) as well as by the interaction between the diaspora community and the host society. This article analyses this concept in its discursive context focusing on Dr Khalil and Antun Sa‘adeh, who were both eminent intellectuals, party founders and editors of several diasporic newspapers and magazines in Argentina and Brazil.
Ambivalent patriotism: Jacob Aall and Dano‐Norwegian identity before 1814
Authors: Peter Burgess J. , Hyvik Jens Johan
Published: October 2004

Abstract. Like many Norwegian elite, Jacob Aall (1773–1844) lived between two national identities – Norwegian and Danish. On the one hand, he was a subject of the Danish crown, educated in Denmark in the refinements of European knowledge and high culture; on the other he was a loyal provincial son of Norway, engaged in building the political and economic autonomy of his homeland. This article examines the two sides of national identity in Jacob Aall's life and work by focusing on the evolution in his understanding of the concept of the Norwegian nation. It argues that the patriotism central to Aall's understanding of modernity and the coming‐to‐age of Norway contains two disparate, but equally necessary sides. The one is characterised by an abiding sentiment of national romantic cultural belonging, the other is a learned commitment to the Enlightenment utilitarian principles that gave force to the Norwegian national movement.
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

Aim

To investigate the effects of donepezil at steady state on the safety, tolerability and pharmacokinetics of a single dose of thioridazine, in healthy subjects.

Methods

An 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.

Results

Donepezil 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.

Conclusions

Repeated 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

Aim

This study evaluated the safety and pharmacokinetics (PK) of donepezil HCl and sertraline HCl when administered separately and in combination.

Methods

This 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).

Results

A 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.

Conclusions

The 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

Interleukin (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 < 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

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

Proteinase 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

Type 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 < 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

Diseases 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

We 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

Human 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

Originally 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.