bluuebunny/crossref_metadata_2025 huggingface dataset:
Timing of host‐seeking behaviour of the mosquitoes Anopheles annulipes sensu lato Walker and Coquillettidia linealis (Skuse) (Diptera: Culicidae) in the Murray River Valley, South Australia
Authors: Williams Craig R
Published: May 2005

Abstract  The timing of host‐seeking behaviour was studied in two mosquito species, Anopheles annulipes sensu lato and Coquillettidia linealis at Mundic Creek, near the Upper River Murray in South Australia. Hourly sampling using carbon dioxide‐baited traps revealed consistent patterns in the timing of host‐seeking. Coquillettidia linealis displayed a very large peak in host‐seeking activity at sunset, followed by a much reduced level throughout the night and a smaller peak at sunrise. Anopheles annulipes s.l. differed by displaying a significantly smaller peak at sunset, followed by higher amount of activity throughout the night compared with Cq. linealis. The two taxa, while both crepuscular and nocturnal, spread their host‐seeking effort out differently throughout the night, indicating that they have different resource requirements.
Multiaxial fatigue of rubber: Part I: equivalence criteria and theoretical aspects
Authors: MARS W. V. , FATEMI A.
Published: May 2005

This paper investigates commonly used approaches for fatigue crack nucleation analysis in rubber, including maximum principal strain (or stretch), strain energy density and octahedral shear strain criteria. The ability of these traditional equivalence criteria, as well as a recent equivalence criterion (the cracking energy density) to predict multiaxial fatigue behaviour is explored. Theoretical considerations are also introduced relating to the applicability of various fatigue life analysis approaches. These include the scalar nature of traditional equivalence criteria, robustness of the criteria investigated for a wide range of multiaxial loadings, effects of crack closure and applications to non‐proportional multiaxial loadings. It is shown that the notion of a stress or strain amplitude tensor used for the analysis of multiaxial loading in metals is not appropriate in the analysis of rubber due to nonlinearity associated with finite strains and near incompressibility. Taken together, these considerations illustrate that traditional criteria are not sufficiently consistent or complete to permit confident analysis of arbitrary multiaxial loading histories, and that an analysis approach specific to the failure plane is needed. Of the three traditional criteria, maximum principal strain is shown to match most closely to the cracking energy density criterion, in terms of a failure locus in principal stretch space.
Effect of stress ratio on fatigue behaviour in SiC particulate‐reinforced aluminium alloy composite
Authors: TOKAJI K.
Published: May 2005

Axial fatigue tests have been performed at three different stress ratios, R, of −1, 0 and 0.4 using smooth specimens of an aluminium alloy composite reinforced with SiC particulates of 20 μm particle size. The effect of stress ratio on fatigue strength was studied on the basis of crack initiation, small crack growth and fracture surface analysis. The stress ratio dependence of fatigue strength that has been commonly observed in other materials was obtained, in which fatigue strength decreased with increasing stress ratio when characterized in terms of stress amplitude. At R=−1, the fatigue strength of the SiCp/Al composite was the same as that of the unreinforced alloy, but at R= 0 and 0.4 decreased significantly, indicating a detrimental effect of tensile mean stress in the SiCp/Al composite. The modified Goodman relation gave a fairly good estimation of the fatigue strength at 107 cycles in the unreinforced alloy, but significantly unconservative estimation in the SiCp/Al composite. At R= 0 and 0.4, cracks initiated at the interfaces between SiC particles and the matrix or due to particle cracking and then grew predominantly along the interfaces, because debonding between SiC particles and the matrix occurred easily under tensile mean stress. Such behaviour was different from that at R=−1. Therefore, it was concluded that the decrease in fatigue strength at high stress ratios and the observed stress ratio dependence in the SiCp/Al composite were attributed to the different fracture mechanisms operated at high stress ratios.
Multiaxial fatigue of rubber: Part II: experimental observations and life predictions
Authors: MARS W. V. , FATEMI A.
Published: May 2005

Fatigue experiments were conducted with an axial‐torsion specimen covering a wide range of stretch biaxiality and a range of fatigue lives between 103 and 2 × 106 cycles. These experiments include combined torsion–compression, pure torsion, combined torsion–tension and pure axial tension. Both in‐phase and out‐of‐phase combinations of axial and torsion loading were considered. The multiaxial fatigue experiments described provide empirical evidence from which an understanding of the mechanics of the fatigue process in rubber can be developed. Each of the four equivalence parameters described in Part I has been applied to the axial‐torsion fatigue experiments described in this paper (Part II). These results provide the basis for an analysis of the effects of multiaxial loading on fatigue life, and an assessment of the degree to which the various equivalence parameters are able to rationalize the results in a unified way. For the combined axial and shear strain histories in this study, the maximum principal strain criterion gave the best correlation to fatigue life. Strain energy density gave the worst correlation. The cracking energy density criterion was generally found to give good correlation of fatigue crack nucleation lives from combined axial‐torsion tests. Because it provides a plane‐specific analysis, this criterion appears to be particularly well suited for use in crack nucleation analyses of multiaxial strain histories.
Evidence on the corrosion‐induced hydrogen embrittlement of the 2024 aluminium alloy
Authors: PETROYIANNIS P. V. , KAMOUTSI E. , KERMANIDIS AL. TH. , PANTELAKIS S. G. , BONTOZOGLOU V. , HAIDEMENOPOULOS G. N.
Published: May 2005

The present work aims to provide evidence of corrosion‐induced hydrogen embrittlement of the aircraft aluminium alloy 2024. An extensive experimental investigation involving metallographic and fractographic analyses as well as mechanical testing was performed. The corrosion exposure led to a moderate reduction in yield and ultimate tensile stress and a dramatic reduction in tensile ductility. Metallographic investigation of the specimens revealed a hydrogen‐rich embrittled zone just below the corrosion layer. Furthermore, fractographic analyses showed an intergranular fracture at the specimen surface followed by a zone of quasi‐cleavage fracture and further below an entirely ductile fracture. Mechanical removal of the corroded layers restored the yield and ultimate stress almost to their initial values but not the tensile ductility. The tensile ductility was restored to the level of the uncorroded material only after heat treatment at 495°C. Measurement of hydrogen evolution with temperature showed that by heating the corroded alloy at 495°C, the trapped hydrogen is released.
The durability of virological success of tenofovir and didanosine dosed at either 400 or 250 mg once daily
Authors: Tung M‐Y , Mandalia S , Bower M , Gazzard B , Nelson M
Published: May 2005

Tenofovir (TDF) co‐administered with didanosine (ddI) 400 mg increases ddI plasma concentrations by up to 60%, raising concerns over toxicity. To limit this interaction, the dosage of ddI may be reduced to 250 mg once daily when co‐prescribed with TDF. In this clinical cohort, highly active antiretroviral therapy regimens containing TDF and ddI 250 mg were significantly better tolerated than combinations with TDF and ddI at a dose of 400 mg. Low‐dose ddI 250 mg once daily plus TDF as part of antiretroviral therapy was effective.
Effects of antiretroviral treatment on blood–brain barrier integrity and intrathecal immunoglobulin production in neuroasymptomatic HIV‐1‐infected patients
Authors: Abdulle S , Hagberg L , Gisslén M
Published: May 2005

Objectives

To study the effect of antiretroviral combination therapy on blood–brain barrier (BBB) integrity and intrathecal immunoglobulin G (IgG) production.

Methods

Lumbar punctures were performed on 38 neurologically asymptomatic, treatment‐naïve HIV‐1‐infected patients prior to and during treatment at intervals of approximately 4 months, 1 year and 2 years. Albumin ratio and IgG index were analysed as markers of BBB integrity and intrathecal IgG synthesis.

Results

HIV‐1 RNA decreased to <50 HIV‐1 RNA copies/mL in the cerebrospinal fluid (CSF) of all patients and in the plasma of all but one patient. Only 5% of patients had elevated albumin ratio values at baseline, while 56% had an elevated IgG index. There was no significant reduction of the albumin ratio or the IgG index. After 2 years of treatment all patients had normal albumin ratio values, while 41% still had increased IgG index levels.

Conclusions

Up to 2 years after the initiation of treatment, the favourable impact of antiretroviral combination treatment on CSF viral load was not accompanied by a similar reduction of intrathecal IgG production. BBB function, measured as the albumin ratio, was not significantly changed in this cohort of neurologically asymptomatic HIV‐1‐infected patients.
Gender difference in HIV‐1 RNA viral loads
Authors: Donnelly CA , Bartley LM , Ghani AC , Le Fevre AM , Kwong GP , Cowling BJ , Van Sighem AI , De Wolf F , Rode RA , Anderson RM
Published: May 2005

Objectives

To test and characterize the dependence of viral load on gender in different countries and racial groups as a function of CD4 T‐cell count.

Methods

Plasma viral load data were analysed for >30 000 HIV‐infected patients attending clinics in the USA [HIV Insight™ (Cerner Corporation, Vienna, VA, USA) and Plum Data Mining LLC (East Meadow, NY, USA) databases] and the Netherlands (Athena database; HIV Monitoring Foundation, Amsterdam, Netherlands). Log‐normal regression models were used to test for an effect of gender on viral load while adjusting for covariates and allowing the effect to depend on CD4 T‐cell count. Sensitivity analyses were performed to test the robustness of conclusions to assumptions regarding viral loads below the lower limit of quantification (LLOQ).

Results

After adjusting for covariates, women had (nonsignificantly) lower viral loads than men (HIV Insight™:−0.053 log10 HIV‐1 RNA copies/mL, P=0.202; Athena: −0.005 log10 copies/mL, P=0.667; Plum:−0.072 log10 copies/mL, P=0.273). However, further investigation revealed that the gender effect depended on CD4 T‐cell count. Women had consistently higher viral loads than men when CD4 T‐cell counts were at most 50 cells/μL, and consistently lower viral loads than men when CD4 T‐cell counts were greater than 350 cells/μL. These effects were remarkably consistent when estimated independently for the racial groups with sufficient data available in the HIV Insight™ and Plum databases.

Conclusions

The consistent relationship between gender‐related differences in viral load and CD4 T‐cell count demonstrated here explains the diverse findings previously published.
Better maintained adherence on switching from twice‐daily to once‐daily therapy for HIV: a 24‐week randomized trial of treatment simplification using stavudine prolonged‐release capsules
Authors: Portsmouth SD , Osorio J , McCormick K , Gazzard BG , Moyle GJ
Published: May 2005

Background

Adherence to antiretroviral therapy is critical to treatment outcomes. Adherence studies in other therapeutic areas of medicine suggest that once‐daily regimens support improved adherence when compared to twice‐daily therapy. An expansion in the range of once‐daily antiretrovirals is making once‐daily therapy possible for persons with HIV infection.

Methods

A 24‐week randomized open‐label simplification study of twice‐daily regimens based on stavudine immediate release or zidovudine to an all once‐daily regimen based on the stavudine prolonged‐release capsule (PRC), in persons with complete virological suppression on regimens also including efavirenz and lamivudine, was carried out. Subjects were assessed for adherence [using the Medication Event Monitoring System® (MEMS®) cap; Aardex Corporation, Union City, CA, USA], quality of life, tolerability and efficacy.

Results

Forty‐three patients were randomly assigned: 21 remained on their original regimen and 22 switched to once‐daily therapy with stavudine PRC. Although high levels of adherence and good quality of life were present at study enrolment, adherence declined to a significantly lesser extent at week 24 in the group that switched to once‐daily therapy. Efficacy was maintained in both groups and there were no differences in tolerability or toxicity.

Conclusions

Subjects switching from twice‐daily therapy to once‐daily therapy demonstrate less of a decline in adherence over 24 weeks. A once‐daily regimen including stavudine PRC is as effective and tolerable as a regimen containing the twice‐daily formulation.
The use of a triple nucleoside‐nucleotide regimen for nonoccupational HIV post‐exposure prophylaxis
Authors: Winston A , McAllister J , Amin J , Cooper DA , Carr A
Published: May 2005

Objectives

Nonoccupational post‐exposure prophylaxis (NPEP) for HIV is recommended after high‐risk sexual exposure. Because of the high incidence of intolerable side effects observed with protease inhibitor‐ and zidovudine‐based NPEP regimens, our unit changed standard NPEP treatment to 28 days of tenofovir‐lamivudine‐stavudine (TDF‐3TC‐d4T). The aim of this study was to compare side effects and numbers of individuals completing NPEP before and after this change.

Methods

Parameters were compared amongst individuals commencing the following NPEP regimens: zidovudine‐lamivudine (ZDV‐3TC), zidovudine‐lamivudine‐nelfinavir (ZDV‐3TC‐NFV) and TDF‐3TC‐d4T.

Results

A total of 385 individuals received ZDV‐3TC (n=36), ZDV‐3TC‐NFV (n=225) or TDF‐3TC‐d4T (n=137) as NPEP for the first time between June 1999 and November 2003. Noncompletion rates were 25%, 32% and 15%, respectively (P=0.001), with odds ratios for noncompletion being 2.0 [95% confidence interval (CI) 0.8–4.8] and 2.7 (95% CI 1.6–4.8) in the first two groups compared with the TDF‐3TC‐d4T group (P=0.008). Adverse events were less common in the TDF‐3TC‐d4T group, with significantly lower rates of nausea and headache, but significantly higher rates of peripheral neuropathy and asymptomatic raised transaminases. There was no HIV seroconversion in any group.

Conclusions

TDF‐3TC‐d4T is significantly better tolerated than ZDV‐3TC or ZDV‐3TC‐NFV as NPEP and results in greater numbers of individuals completing 28 days of treatment.
Determinants of clinical progression in antiretroviral‐naïve HIV‐infected patients starting highly active antiretroviral therapy. Aquitaine Cohort, France, 1996–2002
Authors: Bonnet F , Thiébaut R , Chêne G , Neau D , Pellegrin J‐L , Mercié P , Beylot J , Dabis F , Salamon R , Morlat P ,   for the Groupe d'Epidemiologie Clinique du SIDA en Aquitaine (GECSA)
Published: May 2005

Objectives

To determine the factors associated with clinical progression (AIDS events and death) in antiretroviral‐naïve patients who have begun highly active antiretroviral therapy (HAART).

Methods

HIV‐infected patients naïve to antiretroviral therapy were included in a prospective hospital‐based cohort who began HAART between June 1996 and December 2001. Progression was explained by baseline characteristics using Cox proportional hazards models.

Results

Overall, data for 709 patients were analysed. In multivariate analysis, factors associated with an increased risk of progression were CD4 count <50 cells/μL [hazard ratio (HR)=13.0 (95% confidence interval 3.8–44.3)] and between 50 and 199 cells/μL [HR=5.1 (1.6–16.3)], when compared with patients with CD4 count>350 cells/μL; AIDS events before HAART prescription [HR=2.1 (1.2–3.7)]; CD8 count < 400 cells/μL [HR=1.8 (1.1–3.0)]; and older age (HR=1.2 by 10 years (1.0–1.5)]. In a second model including CD4 percentage, factors associated with progression were CD4<10% [HR=6.3 (2.2–17.9)] and 10%<CD4 <15% [HR=4.2 (1.4–12.5)], when compared with patients with CD4>20%; CD8 count; AIDS events before HAART prescription; and older age. In a third model including the CD4:CD8 ratio, factors associated with progression were CD4:CD8<15% [HR=8.2 (2.3–28.8)] and 15%<CD4:CD8<30% [HR=4.6 (1.3–16.0)], when compared with patients with CD4:CD8>45%; AIDS events before HAART prescription; and older age. The Akaike information criteria for model analysis were 803, 805 and 815, respectively.

Conclusions

Consideration of CD4 level in terms of CD4:CD8 ratio or CD4 percentage can be a good alternative to absolute CD4 count. Other prognostic factors such as older age, CD8 count <400 cells/μL and AIDS events also have to be considered in the decision to initiate HAART.
Predicting short‐term disease progression among HIV‐infected patients in Asia and the Pacific region: preliminary results from the TREAT Asia HIV Observational Database (TAHOD)
Authors: Zhou J , Kumarasamy N ,   on behalf of the TREAT Asia HIV Observational Database
Published: May 2005

Objectives

HIV disease progression has been well documented in Western populations. This study aimed to estimate the short‐term risk of AIDS and death from the TREAT Asia HIV Observational Database (TAHOD), a prospective, multicentre cohort study in Asia and the Pacific region.

Methods

Prospective data were analysed to estimate short‐term disease progression. Endpoints were defined as the time from study entry to diagnosis with AIDS or death. Antiretroviral treatment was fitted as a time‐dependent variable. Predictors of disease progression were assessed using Cox proportional hazards models, and prognostic models were developed using Weibull models.

Results

A total of 1260 patients with prospective follow‐up data contributed 477 person‐years of follow‐up, during which 18 patients died and 34 were diagnosed with AIDS, a combined rate of 10.1 per 100 person‐years. Compared with patients receiving antiretroviral treatment, patients not on treatment had a higher rate of disease progression (17.6 vs. 8.1 per 100 person‐years, respectively). Baseline CD4 count was the strongest predictor of disease progression. Prognostic models, using either a baseline CD4 count as the sole marker or markers including baseline haemoglobin, AIDS‐related symptoms and previous or current antiretroviral treatment, were successful at identifying patients at high risk of short‐term disease progression.

Conclusions

Similar to the situation in Western countries, baseline CD4 count was the strongest predictor of short‐term disease progression. Prognostic models based on readily available clinical data and haemoglobin level should be useful in estimating short‐term clinical risk in HIV‐infected patients in Asia and the Pacific region.
COMMENTS ON GREEN–ZHOU “MONEY AS A MECHANISM IN A BEWLEY ECONOMY”*
Authors: Levine David K.
Published: May 2005

This article discusses the paper by Green and Zhou “Money as a Mechanism in a Bewley Economy” as presented at the second Karaken Conference.
COMMENTS ON “MONEY IS PRIVACY” BY CHARLES KAHN, JAMES McANDREWS, AND WILLIAM ROBERDS: MONETARY THEORY AND GAME THEORY*
Authors: Matsui Akihiko
Published: May 2005

Three classes of models on money closely related to game theoretic models are (i) search theoretic models; (ii) repeated games (in a narrow sense); and (iii) trading post games. This note tries to point out the sense of affinity between the theory of microfoundations of money and the theory of “repeated games” in a broad sense of the term.
BEYOND SEARCH: FIAT MONEY IN ORGANIZED EXCHANGE*
Authors: Howitt Peter
Published: May 2005

A model of fiat money is constructed in which spatial separation and the logistics of communication are made explicit as in search theory, but exchange is organized by profit‐seeking business enterprises as in all market economies. Firms mitigate search costs by opening shops that are easily located. Equilibria may exist in which fiat money is used as a universal medium of exchange. When a monetary equilibrium exists, fiat money is essential. The model provides a foundation to cash‐in‐advance theory, without specifying in advance that one object will be used as the universal medium of exchange.
HETEROGENEITY AND REDISTRIBUTION: BY MONETARY OR FISCAL MEANS?*
Authors: Ireland Peter N.
Published: May 2005

In models with heterogeneous agents, issues of distribution and redistribution jump to the fore, raising the question: Which policies—monetary or fiscal—work most effectively in transferring income between groups? From Townsend's turnpike model, two basic results emerge to help answer this question. First, the zero lower bound on nominal interest rates often appears as an obstacle to redistribution by monetary means. Second, assumptions about the government's ability to raise tax revenue without distortion and to discriminate between agents in distributing that tax revenue play a large role in determining whether agents prefer to redistribute income by fiscal means instead.
INFLATION, OUTPUT, AND WELFARE*
Authors: Lagos Ricardo , Rocheteau Guillaume
Published: May 2005

We study the effects of anticipated inflation on aggregate output and welfare within a search‐theoretic framework. We consider two pricing mechanisms: ex post bargaining and a notion of competitive pricing. Under bargaining, the equilibrium is generically inefficient and an increase in inflation reduces buyers' search intensities, output, and welfare. If prices are posted and buyers can direct their search, search intensities are increasing with inflation for low inflation rates and decreasing for high inflation rates. The Friedman rule achieves the efficient allocation, and inflation always reduces welfare, although it can have a positive effect on output for low inflation rates.
NOMINAL BONDS AND INTEREST RATES*
Authors: Shi Shouyong
Published: May 2005

In this article, I integrate the microfoundation of monetary theory with the model of limited participation to analyze the competition between nominal bonds and money. The market for government nominal bonds is centralized and Walrasian, whereas the goods market is modeled as random matches. The government imposes a legal restriction that requires all government goods to be purchased with money but not with bonds. By contrast, private agents can exchange between themselves with both money and bonds. I show that an arbitrarily small legal restriction is sufficient to prevent matured bonds from being a medium of exchange. I also analyze the effects of monetary policy with and without the legal restriction. Some of those effects differ significantly from traditional monetary models.
MONEY AND BANKING IN SEARCH EQUILIBRIUM*
Authors: He Ping , Huang Lixin , Wright Randall
Published: May 2005

We develop a new theory of money and banking based on the old story in which goldsmiths start accepting deposits for safe keeping, then their liabilities begin circulating as media of exchange, then they begin making loans. We first discuss the history. We then present a model where agents can open bank accounts and write checks. The equilibrium means of payment may be cash, checks, or both. Sometimes multiple equilibria exist. Introducing banks increases the set of parameters for which money is valued–thus, money and banking are complements. We also derive a microfounded version of the usual money multiplier.
LIQUIDITY, MONEY CREATION AND DESTRUCTION, AND THE RETURNS TO BANKING*
Authors: De O. Cavalcanti Ricardo , Erosa Andrés , Temzelides Ted
Published: May 2005

We build on our earlier model of money in which bank liabilities circulate as a medium of exchange. We investigate optimal bank behavior and the resulting provision of liquidity under a range of central bank regulations. In our model, banks issue inside money under fractional reserves, facing the possibility of excess redemptions. Banks consider the float resulting from money creation and make reserve‐management decisions that affect aggregate liquidity conditions. Numerical examples demonstrate positive bank failure rates when returns to banking are low. Central bank interventions may improve banks' returns and welfare through a reduction in bank failure.
Complete Isochromatic Fringe‐order Analysis in Digital Photoelasticity by Fourier Transform and Load Stepping
Authors: Zuccarello B.
Published: May 2005

Abstract:  In this paper, a new fully automated photoelastic technique based on both the Fourier transform and the envelope of the fringe centres, is presented. Using two images of the isochromatics acquired with different loads and a simple calculation routine, the method allows the user the complete determination of the isochromatic fringe retardation on any arbitrary line chosen over the model domain, without the need for supplementary external information or calibration. Various experiments have corroborated the accuracy of the method, estimated theoretically to about 0.07 fringe orders. As a result of its simplicity and sufficient accuracy, the method can be used in the industrial field also by a non‐expert user.
Signal Processing for Remote Condition Monitoring of Railway Points
Authors: McHutchon M. A. , Staszewski W. J. , Schmid F.
Published: May 2005

Abstract:  The dependability of railway points (turnouts or switches) is a key part of any railway system; the Potters Bar crash (10 May 2002) in the UK, which led to seven fatalities is a key example of a failure of this subsystem. Present maintenance of points involves overly frequent inspection by maintenance staff. A remote condition monitoring approach would lead to more efficient inspection routines and directed anticipatory maintenance trips. To assist the creation of a suitable fault‐detection algorithm, the authors analysed existing force and current data for the ‘as commissioned’ case of a turnout and for situations with different fault conditions. Signal processing of this data revealed several different methods that can be used to distinguish between fully functioning points, and different fault conditions of the points. Specifically, clustering of statistical parameters and their application to wavelet levels and coefficients, provided clear discrimination of most critical faults. This demonstrates a good first step towards a condition monitoring‐based maintenance regime for points that is both safer for passengers and maintenance personnel and that has the potential to be more effective and economical.
Loss of ancestral genes in the genomic evolution of Ciona intestinalis
Authors: Hughes Austin L. , Friedman Robert
Published: May 2005

Summary
Comparison of the predicted protein sets encoded by the complete genomes of two vertebrates (human and pufferfish), the urochordate Ciona intestinalis, three nonchordate animals, and two fungi were used to reconstruct a set of gene families present in the common ancestor of chordates. These ancestral families were much more likely to be lost in Ciona than in either vertebrate. In addition, of 256 duplicate gene pairs that arose by duplication prior to the most recent common ancestor of vertebrates and insects, one of the duplicate genes was four times as likely to be lost in Ciona as in the vertebrates. These results show that the genome of Ciona is not representative of the ancestral chordate genome with respect to gene content but rather shows derived features that may reflect adaptation of the specific ecological niche of urochordates.
Expression of estrogen‐receptor related receptors in amphioxus and zebrafish: implications for the evolution of posterior brain segmentation at the invertebrate‐to‐vertebrate transition
Authors: Bardet Pierre‐Luc , Schubert Michael , Horard Béatrice , Holland Linda Z. , Laudet Vincent , Holland Nicholas D. , Vanacker Jean‐Marc
Published: May 2005

Summary
The evolutionary origin of vertebrate hindbrain segmentation is unclear since the amphioxus, the closest living invertebrate relative to the vertebrates, possesses a hindbrain homolog that displays no gross morphological segmentation. Three of the estrogen‐receptor related (ERR) receptors are segmentally expressed in the zebrafish hindbrain, suggesting that their common ancestor was expressed in a similar, reiterated manner. We have also cloned and determined the developmental expression of the single homolog of the vertebrate ERR genes in the amphioxus (AmphiERR). This gene is also expressed in a segmented manner in a region considered homologous to the vertebrate hindbrain. In contrast to the expression of amphioxus islet (a LIM‐homeobox gene that also labels motoneurons), AmphiERR expression persists longer in the hindbrain homolog and does not later extend to additional posterior cells. In addition, AmphiERR and one of its vertebrate homologs (ERRα) are expressed in the developing somitic musculature of amphioxus and zebrafish, respectively. Altogether, our results are consistent with fine structural evidence suggesting that the amphioxus hindbrain is segmented, and indicate that chordate ERR gene expression is a marker for both hindbrain and muscle segmentation. Furthermore, our data support an evolution model of chordate brain segmentation: originally, the program for anterior segmentation in the protochordate ancestors of the vertebrates resided in the developing axial mesoderm which imposed reiterated patterning on the adjacent neural tube; during early vertebrate evolution, this segmentation program was transferred to and controlled by the neural tube.
Making Sense of Lamotrigine Serum Levels
Authors: Abou-Khalil Bassel W.
Published: May 2005

Correlating Lamotrigine Serum Concentrations with Tolerability in Patients with Epilepsy

Hirsch LJ, Weintraub D, Du Y, Buchsbaum R, Spencer HT, Hager M, Straka T, Bazil CW, Adams DJ, Resor SR Jr, Morrell MJ

Neurology 2004;63:1022–1026

Objective

To correlate lamotrigine (LTG) serum concentrations (levels) with tolerability in patients with epilepsy.

Methods

The charts of 811 outpatients with epilepsy who had received LTG and were seen at the Columbia Comprehensive Epilepsy Center after January 1, 2000, were reviewed. Data gathered included levels, dosage, duration of use, concomitant antiepileptic drugs (AEDs), clinical toxicity, specific side effects, and efficacy. Rates of toxicity, specific side effects, and efficacy were calculated and correlated with serum levels.

Results

In total, 3,731 LTG levels were recorded. A regimen was categorized as toxic if the patient experienced side effects that led to a dosage change or discontinuation of LTG. Of 3,919 AED regimens, 9.4% were toxic, and 30.7% of patients had at least one toxic regimen. Toxicity increased with increasing LTG levels ( P < 0.0001): With levels less than 5.0 μg/mL, 7% of patients were toxic; with levels of 5 to 10 μg/mL, 14%; with 10 to 15 μg/mL, 24%; with 15 to 20 μg/mL, 34%; and with more than 20 μg/mL, 59%. The correlation between levels and tolerability was independent of concurrent medication. Increasing efficacy, as measured by seizure freedom for a 6-month period, occurred up to levels of more than 20 μg/mL.

Conclusions

A correlation exists between LTG serum level and tolerability, independent of the use of other AEDs. Adverse effects requiring a dose change are uncommon with the most frequently encountered LTG concentrations (<10 μg/mL) and occur in only 7.4% of patients at levels obtained during the majority of clinical trials (<5 μg/mL). An initial target range of 1.5 to 10 μg/mL is suggested, although higher levels, up to more than 20 μg/mL, are often tolerated and can lead to additional efficacy in refractory patients.
Valproate Poses Risk to Unborn Child
Authors: Meador Kimford
Published: May 2005

The Longer Term Outcome of Children Born to Mothers with Epilepsy

Adab N, Kini U, Vinten J, Ayres J, Baker G, Clayton-Smith J, Coyle H, Fryer A, Gorry J, Gregg J, Mawer G, Nicolaides P, Pickering L, Tunnicliffe L, Chadwick DW

J Neurol Neurosurgsychiatry 2004;75:1575–1583

Objectives

To determine the prevalence of cognitive delay and possible associated dysmorphic features in children exposed to antiepileptic drugs (AEDs) in utero.

Methods

In a retrospective study of children born to mothers with epilepsy, in regional epilepsy clinics in Liverpool and Manchester, U.K., the children were aged between 6 months and 16 years and born to mothers with epilepsy. Structured interviews, hospital records, clinical examination, and psychometric tests (Wechsler) were used to assess exposure and intelligence quotient (IQ). Blinded assessment of photographs was used to score children with characteristic dysmorphic features.

Results

In total, 249 children aged 6 and older were studied: 41 were exposed to sodium valproate (VPA), 52 to carbamazepine, 21 to phenytoin, 49 to polytherapy, and 80 were unexposed. Mean verbal IQ was significantly lower in the VPA group compared with that in unexposed and other monotherapy groups. Multiple regression analysis showed that both VPA exposure and frequent tonic-clonic seizures in pregnancy were significantly associated with a lower verbal IQ, despite adjusting for other confounding factors. A significant negative correlation was found between dysmorphic features and verbal IQ in children exposed to VPA.

Conclusions

This study identifies VPA as a drug carrying potential risks for developmental delay and cognitive impairment and is the first to suggest that frequent tonic-clonic seizures have a similar effect. Our results must be interpreted with caution, given their retrospective nature. Women with epilepsy need careful counseling about individual risk benefit of AED treatment before pregnancy.
Calcium Channel “Gaiting” and Absence Epilepsy
Authors: Noebels Jeffrey L.
Published: May 2005

Dysfunction of the Brain Calcium Channel Cav2.1 in Absence Epilepsy and Episodic Ataxia

Imbrici P, Jaffe SL, Eunson LH, Davies NP, Herd C, Robertson R, Kullmann DM, Hanna MG

Brain 2004;127(Pt 12):2682–2692

The molecular basis of idiopathic generalized epilepsy remains poorly understood. Absence epilepsy with 3-Hz spike–wave EEG is one of the most common human epilepsies and is associated with significant morbidity. Several spontaneously occurring genetic mouse models of absence epilepsy are caused by dysfunction of the P/Q-type voltage-gated calcium channel CaV2.1. Such mice exhibit a primary generalized spike–wave EEG, with frequencies in the range of 5 to 7 Hz, often associated with ataxia, evidence of cerebellar degeneration and abnormal posturing. Previously, we identified a single case of severe primary generalized epilepsy with ataxia associated with CaV2.1 dysfunction, suggesting a possible link between this channel and human absence epilepsy. We now report a family in which absence epilepsy segregates in an autosomal dominant fashion through three generations. Five members exhibit a combination of absence epilepsy (with 3-Hz spike–wave) and cerebellar ataxia. In patients with the absence epilepsy/ataxia phenotype, genetic marker analysis was consistent with linkage to the CACNA1A gene on chromosome 19, which encodes the main pore-forming α1A subunit of CaV2.1 channels (CaV2.1 α1). DNA sequence analysis identified a novel point mutation resulting in a radical amino acid substitution (E147K) in CaV2.1 α1, which segregated with the epilepsy/ataxia phenotype. Functional expression studies using human CACNA1A cDNA demonstrated that the E147K mutation results in impairment of calcium channel function. Impaired function of the brain calcium channel CaV2.1 may have a central role in the pathogenesis of certain cases of primary generalized epilepsy, particularly when associated with ataxia, which may be wrongly ascribed to anticonvulsant medication.
Regulation of Brain Water: Is there a Role for Aquaporins in Epilepsy?
Authors: Dudek F. Edward , Rogawski Michael A.
Published: May 2005

Aquaporin-4 Is Increased in the Sclerotic Hippocampus in Human Temporal Lobe Epilepsy

Lee TS, Eid T, Mane S, Kim JH, Spencer DD, Ottersen OP, de Lanerolle NC

Acta Neuropathol (Berl) 2004;108:493–502

The hippocampus of patients with mesial temporal lobe epilepsy is often hardened and shrunken, a condition known as sclerosis. MRI reveals an increase in the T2-weighted signal, whereas diffusion-weighted imaging shows a higher apparent diffusion coefficient in sclerotic hippocampi, indicating increased water content. As water transport appears to be coupled to K+ clearance and neuronal excitability, the molecular basis of the perturbed water homeostasis in the sclerotic hippocampus was explored. The expression of aquaporin-4 (AQP-4), the predominant water channel in the brain, was studied with quantitative real-time polymerase chain reaction analysis, light-microscopic immunohistochemistry, and high-resolution immunogold labeling. A significant increase in AQP-4 was observed in sclerotic, but not in nonsclerotic, hippocampi obtained from patients with medically intractable temporal lobe epilepsy. This increase was positively correlated with an increase in the astrocyte marker glial fibrillary acidic protein. AQP-4 was localized to the plasma membranes of astrocytes including the perivascular endfeet. Gene expression associated with increased AQP-4 was evaluated by high-throughput gene-expression analysis with Affymetrix GeneChip U133A, and related gene networks were investigated with Ingenuity Pathways Analysis. AQP-4 expression was associated with a decrease in expression of the dystrophin gene, a protein implicated in the anchoring of AQP-4 in perivascular endfeet. The decreased expression of dystrophin may indicate a loss of polarity in the distribution of AQP-4 in astrocytes. We conclude that the perturbed expression of AQP-4 and dystrophin may be one factor underlying the loss of ion and water homeostasis in the sclerotic hippocampus and hypothesize that the reported changes may contribute to the epileptogenic properties of the sclerotic tissue.
Brain-derived Neurotrophic Factor and Epilepsy—A Missing Link?
Authors: Scharfman Helen E.
Published: May 2005

It has been known for some time that brain-derived neurotrophic factor (BDNF) is critical to normal development of the CNS, and more recently, studies also have documented the ability of BDNF to modify adult CNS structure and function. Therefore, it is no surprise that BDNF has been linked to diseases, such as epilepsy, which may involve abnormal cortical development or altered brain structure and function after maturity. This review evaluates the evidence, particularly from recent studies, that BDNF contributes to the development of temporal lobe epilepsy (TLE).
Neuroleptic dysphoria: revisiting the concept 50 years later
Authors: Awad A. G. , Voruganti L. N. P.
Published: May 2005

Objective:  To review the concept of neuroleptic dysphoria, its historical development and the current state of the art.

Method:  This paper is based on extensive but selective literature review and also draws on our extensive clinical and research experiences.

Results:  Although the construct of neuroleptic dysphoria was recognized shortly following the introduction of the first antipsychotic, chlorpromazine, it took several years for the concept to receive adequate research and clinical attention. Without having direct evidence to link neuroleptic dysphoria to dopamine, it was generally understood that dopamine played a significant role in its genesis. In recent neuroimaging studies and dopamine depletion strategies, the role of dopamine in the genesis of neuroleptic dysphoria has been directly confirmed.

Conclusion:  Neuroleptic dysphoria is a valid construct, which has significant implications for treatment and outcome. It is now clear that it relates to dopamine activities in the nigrostriatal complex. Recent research has also raised the issue of whether neuroleptic dysphoria is a variant of extrapyramidal symptoms. Meanwhile, the role of dopamine in both the genesis of neuroleptic dysphoria and addictive behaviour has raised the issue of both conditions being different facets of the schizophrenic disease process. The recent interface of addiction and psychiatry research may have opened a new science: the science of subjective tolerability disorders.
Subjective well‐being under neuroleptic treatment and its relevance for compliance
Authors: Naber D. , Karow A. , Lambert M.
Published: May 2005

Objective:  To review the concept of ‘subjective well‐being under neuroleptic treatment’, its development and clinical relevance, particularly regarding compliance.

Method:  The manuscript includes a review of the limited literature and recent open and controlled clinical trials.

Results:  The patients’ perspective of antipsychotic treatment was largely neglected for a long time. Scientific interest in this field of strong clinical relevance started mainly with the development of atypical antipsychotics. Recent research indicates that subjective well‐being (SW) is a major determinant of medication compliance in schizophrenia. There are several self‐report instruments with sufficient internal consistency and good construct validity. Effects of antipsychotic treatment on psychopathology and SW are only partly related. Most patients strongly prefer the atypical over typical antipsychotics. The assessment of SW is helpful for selecting the optimal drug for the individual patient.

Conclusion:  SW, under antipsychotic treatment, is a valid construct; its assessment provides an independent outcome variable, which is relevant to compliance.
Long‐term treatment with deferiprone in a L1 veteran
Authors: Meo Anna , Ruggeri Annalisa , Rosa Maria Angela La , Zanghì Laura , Kordes Uwe , Fischer Roland
Published: May 2005

Abstract:  We studied a patient with mild β‐thalassaemia major under treatment with the oral chelator deferiprone (DFP or L1) for about 10 yr (L1 veteran). Due to poor compliance with desferrioxamine, the patient started compassionate use of DFP at an age of 23 yr with a serum ferritin of 5200 μg/L. Monitoring iron overload by SQUID biosusceptometry revealed a dramatic decrease of liver iron concentrations from 4500 to 950 μg/gliver within 9.5 yr. A good clinical response to chelation treatment with DFP was observed together with an improvement of liver and cardiac function and a reduction in the hepatitis virus load.
Sequential organ failure predicts mortality of patients with a haematological malignancy needing intensive care
Authors: Cornet Alexander D. , Issa Aart I. , van de Loosdrecht Arjan A. , Ossenkoppele Gert J. , Strack Van Schijndel Rob J. M. , Johan Groeneveld A. B.
Published: May 2005

Abstract:  Objectives: Poor survival of patients with a haematological malignancy admitted to the intensive care unit (ICU) prompts for proper admission triage and prediction of ICU treatment failure and long‐term mortality. We therefore tried to find predictors of the latter outcomes. Methods: A retrospective analysis of charts and a prospective follow‐up study were done, of haemato‐oncological patients, admitted to our ICU in a 7‐year period with a follow‐up until 2 yr thereafter. Clinical parameters during the first four consecutive days were taken to calculate the simplified acute physiology (SAPS II) and the sequential organ failure assessment (SOFA) scores, of proven predictive value in general ICU populations. Results: From a total of 58 patients (n = 47 with acute myelogenous leukaemia or non‐Hodgkin lymphoma), admitted into ICU mostly because of respiratory insufficiency, sepsis, shock or combinations, 36 patients had died during their stay in the ICU. Of ICU survivors (n = 22), 20 patients died during follow‐up so that the 1‐year survival rate was only 12%. The SAPS II and particularly the SOFA scores were of high predictive value for ICU and long‐term mortality. Conclusions: Patients with life‐threatening complications of haematological malignancy admitted to ICU ran a high risk for death in the ICU and on the long‐term, and the risk can be well predicted by SOFA. The latter may help us to decide on intensive care in individual cases, in order to avoid potentially futile care for patients with a SOFA score of 15 or higher.
Grading of symptoms in hyperleukocytic leukaemia: a clinical model for the role of different blast types and promyelocytes in the development of leukostasis syndrome
Authors: Novotny J. R. , Müller‐Beißenhirtz H. , Herget‐Rosenthal S. , Kribben A. , Dührsen U.
Published: May 2005

Abstract:  Objective: Patients with hyperleukocytic leukaemia were graded according to the severity of symptoms possibly caused by leukostasis to evaluate the effectiveness of therapy and to test the relative contribution of blast type and count of blasts and promyelocytes in the development of leukostasis syndrome. Methods: Ninety‐five patients (59 male, 36 female, median age 52 yr) with hyperleukocytic leukaemia [leukocytes above 50 × 109/L, 48 acute myeloid leukaemia (AML), 31 chronic myeloid leukaemia (CML), 13 acute lymphoblastic leukaemia (ALL), three chronic myelomonocytic leukaemia (CMML)] were grouped according to the presence or absence and severity of neurologic, pulmonary and other symptoms into four categories (no, possible, probable and highly probable leukostasis syndrome). Age, white blood count (WBC), haemoglobin, blast count and total of blasts plus promyelocytes of these groups were compared by Mann–Whitney U‐test. Results: Patients with myeloid leukaemia (AML M1/M2, CML) which scored as highly probable leukostasis showed significantly higher WBC (P = 0.011), lower haemoglobin (P = 0.004), higher peripheral blast counts (P = 0.004) and higher total of peripheral blasts plus promyelocytes (P < 0.001) compared with the lower probability groups. In leukaemia involving the monocytic lineage (AML M4/M5, CMML) no significant differences were found in any of these factors between patients with highly probable leukostasis and the other patients. Conclusions: Our results show that a four‐stage clinical grading scale is a valuable tool for analysing hyperleukocytic patient populations and evaluate the effectiveness of therapy more precisely. We further demonstrate that the mechanisms of leukostasis are different in myeloid leukaemia as compared with leukaemia with involvement of the monocytic lineage.
Management of patients with polycythaemia vera: results of a survey among Swedish haematologists
Authors: Andreasson Björn , Löfvenberg Eva , Westin Jan
Published: May 2005

Abstract:  The prevailing attitudes regarding diagnostic and therapeutic procedures in patients with polycythaemia vera (PV) among Swedish haematologists were surveyed by way of a mailed questionnaire in August 2002. Among diagnostic procedures frequent use is reported for arterial O2 saturation, spleen size determination, bone marrow histology, serum erythropoietin, serum cobalamins and leukocyte alkaline phosphatase score, while direct determination of the red blood cell mass is used infrequently (seldom or never by 82%). Among therapeutic modalities hydroxyurea and phlebotomy alone were most frequently used. The 32P therapy was used at least sometimes by 57% of the physicians, and more widely in the university clinics. Anagrelide and alfa‐interferon was used in a minority of patients only. The use of prophylactic acetylsalicylic acid was very variable. The majority of the physicians had an aim for their phlebotomy treatment at a level of 0.45 or less, but 21% used a level of 0.46–0.49 and 8% a level of 0.55–0.60 (in younger patients). The platelet level, at which myelosuppressive therapy was initiated, also varied, from 400 × 109/L to >1500 × 109/L. It can be concluded that in practical clinical work in Sweden the diagnosis of PV is established by frequent use of serum erythropoietin, bone marrow examination and spleen size determination. The use of different therapeutic modalities is very variable. Many physicians carry out their phlebotomy treatment with less intensity compared with national and international recommendations.