bluuebunny/crossref_metadata_2025 huggingface dataset:
Activated Src abrogates the Myc requirement for the G
0
/G
1
transition but not for the G
1
/S transition
Authors: Prathapam Tulsiram , Tegen Sarah , Oskarsson Thordur , Trumpp Andreas , Martin G. Steven
Published: February 2006

The transcription factor Myc plays a central role in the control of cellular proliferation. Myc expression is induced by growth factors in a pathway mediated by cellular Src (c-Src), but it is not clear whether Myc induction or activity is required for malignant transformation by activated Src. We introduced v-Src into a c-
myc
−/−
derivative of Rat-1 fibroblasts and into 3T9 mouse fibroblasts harboring a conditionally excisable c-
myc
allele. Expression of activated viral Src in Myc-deficient cells led to loss of actin stress fibers and surface fibronectin, indicating that Myc is dispensable for v-Src-induced morphological transformation. However, v-Src failed to rescue the proliferative defect resulting from the loss of Myc. In Myc-deficient cells, despite its inability to overcome this proliferation block, v-Src was able to regulate the expression of certain Myc transcriptional targets and induce the expression of active cyclin D/Cdk4 and Cdk6 complexes; it also induced the phosphorylation of Rb, albeit at reduced levels. In contrast, however, in the absence of Myc, the level of Cdk2 kinase activity was drastically reduced. This reduction in Cdk2 activity was associated with a decrease in the expression of Cdk7, Cdc25A, and cyclin A. Coexpression of Cdk2 plus cyclin E and/or cyclin A rescued the G
1
/S block and allowed the cells to enter mitosis. These results indicate that in the absence of Myc, v-Src can activate early G
1
cell cycle regulators but fails to activate regulators of the late G
1
/S transition.
Variable host–pathogen compatibility in
Mycobacterium tuberculosis
Authors: Gagneux Sebastien , DeRiemer Kathryn , Van Tran , Kato-Maeda Midori , de Jong Bouke C. , Narayanan Sujatha , Nicol Mark , Niemann Stefan , Kremer Kristin , Gutierrez M. Cristina , Hilty Markus , Hopewell Philip C. , Small Peter M.
Published: February 2006

Mycobacterium tuberculosis
remains a major cause of morbidity and mortality worldwide. Studies have reported human pathogens to have geographically structured population genetics, some of which have been linked to ancient human migrations. However, no study has addressed the potential evolutionary consequences of such longstanding human–pathogen associations. Here, we demonstrate that the global population structure of
M. tuberculosis
is defined by six phylogeographical lineages, each associated with specific, sympatric human populations. In an urban cosmopolitan environment, mycobacterial lineages were much more likely to spread in sympatric than in allopatric patient populations. Tuberculosis cases that did occur in allopatric hosts disproportionately involved high-risk individuals with impaired host resistance. These observations suggest that mycobacterial lineages are adapted to particular human populations. If confirmed, our findings have important implications for tuberculosis control and vaccine development.
The structure of a ring-opened proliferating cell nuclear antigen–replication factor C complex revealed by fluorescence energy transfer
Authors: Zhuang Zhihao , Yoder Bonita L. , Burgers Peter M. J. , Benkovic Stephen J.
Published: February 2006

Numerous proteins that function in DNA metabolic pathways are known to interact with the proliferating cell nuclear antigen (PCNA). The important function of PCNA in stimulating various cellular activities requires its topological linkage with DNA. Loading of the circular PCNA onto duplex DNA requires the activity of a clamp-loader [replication factor C (RFC)] complex and the energy derived from ATP hydrolysis. The mechanistic and structural details regarding PCNA loading by the RFC complex are still developing. In particular, the positive identification of a long-hypothesized structure of an open clamp–RFC complex as an intermediate in loading has remained elusive. In this study, we capture an open yeast PCNA clamp in a complex with RFC through fluorescence energy transfer experiments. We also follow the topological transitions of PCNA in the various steps of the clamp-loading pathway through both steady-state and stopped-flow fluorescence studies. We find that ATP effectively drives the clamp-loading process to completion with the formation of the closed PCNA bound to DNA, whereas ATPγS cannot. The information derived from this work complements that obtained from previous structural and mechanistic studies and provides a more complete picture of a eukaryotic clamp-loading pathway using yeast as a paradigm.
Distributed Dynamic Storage in Wireless Networks
Authors: Georgiou Constantinos , Kranakis Evangelos , Marceí-n-Jiménez Ricardo , Rajsbaum Sergio , Urrutia Jorge
Published: February 2006

This paper assumes a set of identical wireless hosts, each one aware of its location. The network is described by a unit distance graph whose vertices are points on the plane two of which are connected if their distance is at most one. The goal of this paper is to design local distributed solutions that require a constant number of communication rounds, independently of the network size or diameter. This is achieved through a combination of distributed computing and computational complexity tools. Starting with a unit distance graph, the paper shows: 1. How to extract a triangulated planar spanner; 2. Several algorithms are proposed to construct spanning trees of the triangulation. Also, it is described how to construct three spanning trees of the Delaunay triangulation having pairwise empty intersection, with high probability. These algorithms are interesting in their own right, since trees are a popular structure used by many network algorithms; 3. A load balanced distributed storage strategy on top of the trees is presented, that spreads replicas of data stored in the hosts in a way that the difference between the number of replicas stored by any two hosts is small. Each of the algorithms presented is local, and hence so is the final distributed storage solution, obtained by composing all of them. This implies that the solution adapts very quickly, in constant time, to network topology changes. We present a thorough experimental evaluation of each of the algorithms supporting our claims.
Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin
Authors: Dunn Shannon E. , Youssef Sawsan , Goldstein Matthew J. , Prod'homme Thomas , Weber Martin S. , Zamvil Scott S. , Steinman Lawrence
Published: February 2006

3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase is a critical enzyme in the mevalonate pathway that regulates the biosynthesis of cholesterol as well as isoprenoids that mediate the membrane association of certain GTPases. Blockade of this enzyme by atorvastatin (AT) inhibits the destructive proinflammatory T helper cell (Th)1 response during experimental autoimmune encephalomyelitis and may be beneficial in the treatment of multiple sclerosis and other Th1-mediated autoimmune diseases. Here we present evidence linking specific isoprenoid intermediates of the mevalonate pathway to signaling pathways that regulate T cell autoimmunity. We demonstrate that the isoprenoid geranylgeranyl-pyrophosphate (GGPP) mediates proliferation, whereas both GGPP and its precursor, farnesyl-PP, regulate the Th1 differentiation of myelin-reactive T cells. Depletion of these isoprenoid intermediates in vivo via oral AT administration hindered these T cell responses by decreasing geranylgeranylated RhoA and farnesylated Ras at the plasma membrane. This was associated with reduced extracellular signal–regulated kinase (ERK) and p38 phosphorylation and DNA binding of their cotarget c-fos in response to T cell receptor activation. Inhibition of ERK and p38 mimicked the effects of AT and induced a Th2 cytokine shift. Thus, by connecting isoprenoid availability to regulation of Th1/Th2 fate, we have elucidated a mechanism by which AT may suppress Th1-mediated central nervous system autoimmune disease.
Interaction of Acid-sensing Ion Channel (ASIC) 1 with the Tarantula Toxin Psalmotoxin 1 is State Dependent
Authors: Chen Xuanmao , Kalbacher Hubert , Gründer Stefan
Published: February 2006

Acid-sensing ion channels (ASICs) are Na+ channels gated by extracellular H+. Six ASIC subunits that are expressed in neurons have been characterized. The tarantula toxin psalmotoxin 1 has been reported to potently and specifically inhibit homomeric ASIC1a and has been useful to characterize ASICs in neurons. Recently we have shown that psalmotoxin 1 inhibits ASIC1a by increasing its apparent affinity for H+. However, the mechanism by which PcTx1 increases the apparent H+ affinity remained unclear. Here we show that PcTx1 also interacts with ASIC1b, a splice variant of ASIC1a. However, PcTx1 does not inhibit ASIC1b but promotes its opening; under slightly acidic conditions, PcTx1 behaves like an agonist for ASIC1b. Our results are most easily explained by binding of PcTx1 with different affinities to different states (closed, open, and desensitized) of the channel. For ASIC1b, PcTx1 binds most tightly to the open state, promoting opening, whereas for ASIC1a, it binds most tightly to the open and the desensitized state, promoting desensitization.
Quasigroup associativity and biased expansion graphs
Authors: Zaslavsky Thomas
Published: February 2006

We present new criteria for a multary (or polyadic) quasigroup to be isotopic to an iterated group operation. The criteria are consequences of a structural analysis of biased expansion graphs. We mention applications to transversal designs and generalized Dowling geometries.
Symbiont modifies host life-history traits that affect gene flow
Authors: Leonardo Teresa E , Mondor Edward B
Published: February 2006

The evolution of herbivore–host plant specialization requires low levels of gene flow between populations on alternate plant species. Accordingly, selection for host plant specialization is most effective when genotypes have minimal exposure to, and few mating opportunities with individuals from, alternate habitats. Maternally transmitted bacterial symbionts are common in insect herbivores and can influence host fecundity under a variety of conditions. Symbiont-mediated effects on host life-history strategies, however, are largely unknown. Here, we show that the facultative bacterial symbiont
Candidatus
Regiella insecticola strikingly alters both dispersal and mating in the pea aphid,
Acyrthosiphon pisum
. Pea aphids containing
Regiella
produced only half the number of winged offspring in response to crowding and, for two out of three aphid lineages, altered the timing of sexual reproduction in response to conditions mimicking seasonal changes, than did aphids lacking
Regiella
. These symbiont-associated changes in dispersal and mating are likely to have played a key role in the initiation of genetic differentiation and in the evolution of pea aphid–host plant specialization. As symbionts are widespread in insects, symbiont-induced life history changes may have promoted specialization, and potentially speciation, in many organisms.
Evidence for a Müllerian mimetic radiation in Asian pitvipers
Authors: Sanders K.L , Malhotra A , Thorpe R.S
Published: February 2006

Müllerian mimicry, in which toxic species gain mutual protection from shared warning signals, is poorly understood in vertebrates, reflecting a paucity of examples. Indirect evidence for mimicry is found if monophyletic species or clades show parallel geographic variation in warning patterns. Here, we evaluate a hypothesis of Müllerian mimicry for the pitvipers in Southeast Asia using a phylogeny derived from DNA sequences from four combined mitochondrial regions. Mantel matrix correlation tests show that conspicuous red colour pattern elements are significantly associated with sympatric and parapatric populations in four genera. To our knowledge, this represents the first evidence of a Müllerian mimetic radiation in vipers. The putative mimetic patterns are rarely found in females. This appears paradoxical in light of the Müllerian prediction of monomorphism, but may be explained by divergent selection pressures on the sexes, which have different behaviours. We suggest that biased predation on active males causes selection for protective warning coloration, whereas crypsis is favoured in relatively sedentary females.
Epidemic dynamics and antigenic evolution in a single season of influenza A
Authors: Boni Maciej F , Gog Julia R , Andreasen Viggo , Feldman Marcus W
Published: February 2006

We use a mathematical model to study the evolution of influenza A during the epidemic dynamics of a single season. Classifying strains by their distance from the epidemic-originating strain, we show that neutral mutation yields a constant rate of antigenic evolution, even in the presence of epidemic dynamics. We introduce host immunity and viral immune escape to construct a non-neutral model. Our population dynamics can then be framed naturally in the context of population genetics, and we show that departure from neutrality is governed by the covariance between a strain's fitness and its distance from the original epidemic strain. We quantify the amount of antigenic evolution that takes place in excess of what is expected under neutrality and find that this excess amount is largest under strong host immunity and long epidemics.
Prediction and design of macromolecular structures and interactions
Authors: Baker David
Published: February 2006

In this article, I summarize recent work from my group directed towards developing an improved model of intra and intermolecular interactions and applying this improved model to the prediction and design of macromolecular structures and interactions. Prediction and design applications can be of great biological interest in their own right, and also provide very stringent and objective tests which drive the improvement of the model and increases in fundamental understanding. I emphasize the results from the prediction and design tests that suggest progress is being made in high-resolution modelling, and that there is hope for reliably and accurately computing structural biology.
Towards genome-scale structure prediction for transmembrane proteins
Authors: Hurwitz Naama , Pellegrini-Calace Marialuisa , Jones David T
Published: February 2006

In this paper we briefly review some of the recent progress made by ourselves and others in developing methods for predicting the structures of transmembrane proteins from amino acid sequence. Transmembrane proteins are an important class of proteins involved in many diverse biological functions, many of which have great impact in terms of disease mechanism and drug discovery. Despite their biological importance, it has proven very difficult to solve the structures of these proteins by experimental techniques, and so there is a great deal of pressure to develop effective methods for predicting their structure. The methods we discuss range from methods for transmembrane topology prediction to new methods for low resolution folding simulations in a knowledge-based force field. This potential is designed to reproduce the properties of the lipid bilayer. Our eventual aim is to apply these methods in tandem so that useful three-dimensional models can be built for a large fraction of the transmembrane protein domains in whole proteomes.
Lost in Translation: A Multi‐Level Case Study of the Metamorphosis of Meanings and Action in Public Sector Organizational Innovation
Authors: Pope Catherine , Robert Glenn , Bate Paul , Le May Andrée , Gabbay John
Published: February 2006

This paper explores the early implementation of an organizational innovation in the UK National Health Service (NHS) – Treatment Centres (TCs) – designed to dramatically reduce waiting lists for elective care. The paper draws on case studies of 8 TCs (each at varying stages of their development) and aims to explore how meanings about TCs are created and evolve, and how these meanings impact upon the development of the organizational innovation. Research on organizational meanings needs to take greater account of the fact that modern organizations like the NHS are complex multi‐level phenomena, comprising layers of interlacing networks. To understand the pace, direction and impact of organizational innovation and change we need to study the interconnections between meanings across different organizational levels. The data presented in this paper show how the apparently simple, relatively unformed, concept of a TC framed by central government is translated and transmuted by subsequent layers in the health service administration, and by players in local health economies, and, ultimately, in the TCs themselves, picking up new rationales, meanings and significance as it goes along. The developmental histories of TCs reveal a range of significant re‐workings of macro policy with the result that there is considerable diversity and variation between local TC schemes. The picture is of important disconnections between meanings, that in many ways mirror Weick's (1976) ’loosely coupled systems’. The emergent meanings and the direction of micro‐level development of TCs appear more strongly determined by interactions within the local TC environment, notably between what we identify as groups of ’idealists’, ’pragmatists’, ’opportunists’ and ’sceptics’ than by the framing (Goffman 1974) provided by macro and meso organizational levels. While this illustrates the limitations of top down and policy‐driven attempts at change, and highlights the crucial importance of the front‐line local ’micro‐systems’ (Donaldson and Mohr 2000) in the overall scheme of implementing organizational innovations, the space or headroom provided by frames at the macro and meso levels can enable local change, albeit at variable speed and with uncertain outcomes.
Ministers and Top Officials in the Dutch Core Executive: Living Together, Growing Apart?
Authors: Hart Paul ’t , Wille Anchrit
Published: February 2006

This paper reports the results of a comprehensive, qualitative (100 interviews; 9 interactive workshops) study among Dutch ministers and top departmental officials. Its key question is how both groups conceive of their respective roles and working relationships. This question became a high‐profile issue in the late 1990s after a series of overt clashes between senior political and bureaucratic executives. To what extent does the old, Weberian set of norms and expectations concerning the interaction between politics and bureaucracy still govern the theories and interaction patterns in use among ministers and top officials within the core executive? What new role conceptions are in evidence, and how can we explain their occurrence and diffusion in the Dutch core executive?
Does Ownership Matter for the Delivery of Professionalized Public Services? Cost‐efficiency and Effectiveness in Private and Public Dental Care for Children in Denmark
Authors: Bøgh Andersen Lotte , Blegvad Marianne
Published: February 2006

Recent decades have witnessed considerable interest in the cost‐efficiency and effectiveness of public services. Private provision is often claimed to be more cost‐efficient than public provision, but these efficiency gains are accused of being at the expense of effectiveness. Most of the evidence comes from relatively simple, technical services, because effectiveness is often difficult to define and measure for services produced by professionals. In addition, type of ownership might very well affect services produced by professionals differently as a result of professional standards and other regulation. The case in question, child dental care in Denmark, is a professionalized service which is remarkable for its clear and quantifiable measure of effectiveness. The findings show that neither cost‐efficiency nor effectiveness of public and private producers differs. The data represent cost and outcome measures controlled for structural variables for the 275 Danish municipalities between 1996 and 2002.
Public‐Nonprofit Partnerships for Collective Action in Dynamic Contexts of Emergencies
Authors: Kapucu Naim
Published: February 2006

This article seeks to understand the problem of building cooperation among public and nonprofit organizations to achieve public service goals in emergencies. It also examines the factors that contribute to successful public‐nonprofit partnerships (PNP) and what factors inhibit their development. The theoretical framework draws upon the literature on social capital, network theory and organizational collaboration. The article uses the network analysis perspective to assess the relationships among organizations in terms of their strength, direction and density in the rapid evolution of emergency response operations. The theoretical framework is applied to analyse the interorganizational responses to the 11 September 2001 World Trade Center (WTC) terrorist attacks in New York City. Emergency response operations required coordinated action among many actors across multiple jurisdictions under conditions of urgent stress, high demand and tight time constraints. This type of network analysis can constitute a field of substantial interest and importance to democratic societies that are seeking to manage problems of public service delivery in emergencies using innovative means.
The influence of Gujarati and Tamil L1s on Indian English: a preliminary study
Authors: Wiltshire Caroline R. , Harnsberger James D.
Published: February 2006

Abstract:  English as spoken as a second language in India has developed distinct sound patterns in terms of both segmental and prosodic characteristics. We investigate the differences between two groups varying in native language (Gujarati, Tamil) to evaluate to what extent Indian English (IE) accents are based on a single target phonological‐phonetic system (i.e., General Indian English), and/or vary due to transfer from the native language. Consonants, vowels and intonation patterns from five Gujarati English (GE) and five Tamil English (TE) speakers of IE were transcribed and, in a subset of cases, acoustically analyzed. The results showed transfer effects in GE back vowels, TE rhotics and the proportion of rising versus falling pitch accents in GE intonation. The effect of the General Indian English model was evident in the front vowels of both GE and TE and in the presence of initial voiced stops in TE. Thus, the data reveal both phonetic and phonological influences of IE speakers’ native language on their accent in IE, even in proficient speakers; these influences appear to supersede IE norms and can be found in both the segmental and suprasegmental properties of their speech.
Regulatory mechanisms and functions of intermediate filaments: A study using site‐ and phosphorylation state‐specific antibodies
Authors: Izawa Ichiro , Inagaki Masaki
Published: February 2006

Intermediate filaments (IF) form the structural framework of the cytoskeleton. Although histopathological detection of IF proteins is utilized for examining cancer specimens as reliable markers, the molecular mechanisms by which IF are involved in the biology of cancer cells are still unclear. We found that site‐specific phosphorylation of IF proteins induces the disassembly of filament structures. To further dissect the in vivo spatiotemporal dynamics of IF phosphorylation, we developed site‐ and phosphorylation state‐specific antibodies. Using these antibodies, we detected kinase activities that specifically phosphorylate type III IF, including vimentin, glial fibrillary acidic protein and desmin, during mitosis. Cdk1 phosphorylates vimentin‐Ser55 from prometaphase to metaphase, leading to the recruitment of Polo‐like kinase 1 (Plk1) to vimentin. Upon binding to Phospho‐Ser55 of vimentin, Plk1 is activated, and then phosphorylates vimentin‐Ser82. During cytokinesis, Rho‐kinase and Aurora‐B specifically phosphorylate IF at the cleavage furrow. IF phosphorylation by Cdk1, Plk1, Rho‐kinase and Aurora‐B plays an important role in the local IF breakdown, and is essential for the efficient segregation of IF networks into daughter cells. As another part of our research on IF, we have set out to find the binding partners with simple epithelial keratin 8/18. We identified tumor necrosis factor receptor type 1‐associated death domain protein (TRADD) as a keratin 18‐binding protein. Together with data from other laboratories, it is proposed that simple epithelial keratins may play a role in modulating the response to some apoptotic signals. Elucidation of the precise molecular functions of IF is expected to improve our understanding of tumor development, invasion and metastasis. (Cancer Sci 2006; 97: 167–174)
Cannabis use and other illicit drug use: testing the cannabis gateway hypothesis
Authors: Fergusson David M. , Boden Joseph M. , Horwood L. John
Published: February 2006

Aim  To examine the associations between the frequency of cannabis use and the use of other illicit drugs.

Design  A 25‐year longitudinal study of the health, development and adjustment of a birth cohort of 1265 New Zealand children.

Measurements  Annual assessments of the frequency of cannabis use were obtained for the period 14–25 years, together with measures of the use of other illicit drugs from the same time period.

Findings  The frequency of cannabis use was associated significantly with the use of other illicit drugs, other illicit drug abuse/dependence and the use of a diversity of other drugs. This association was found to be particularly strong during adolescence but declined rapidly as age increased. Statistical control for confounding by both fixed and time dynamic factors using random‐ and fixed‐effects regression models reduced the strength of association between frequency of cannabis use and other illicit drug use, but a strong association between frequency of cannabis use and other illicit drug use remained even after control for non‐observed and time‐dynamic sources of confounding. 

Conclusions  Regular or heavy cannabis use was associated with an increased risk of using other illicit drugs, abusing or becoming dependent upon other illicit drugs, and using a wider variety of other illicit drugs. The risks of use, abuse/dependence, and use of a diversity of other drugs declined with increasing age. The findings may support a general causal model such as the cannabis gateway hypothesis, but the actual causal mechanisms underlying such a gateway, and the extent to which these causal mechanisms are direct or indirect, remain unclear.
Allocating treatment options to patient profiles: clinical art or science?
Authors: Bühringer Gerhard
Published: February 2006

Background  For many researchers, the disappointing results of Project MATCH were the death blow for any further activities in the field of patient–treatment interactions. On the other hand, we have an increased knowledge of patient heterogeneity and a greater variety of treatment options than before, and allocation guidelines for an ongoing process of patient‐placement decisions are of high practical relevance.

Aims  To analyse deficits in the current research and to provide suggestions for future action.

Findings  It is argued that (1) certain major design aspects of Project MATCH and other research studies—such as stringent patient exclusion criteria and low treatment ‘dosage’—minimize the chances of detecting possible patient–treatment interactions and (2) Project MATCH obscures our view of previous treatment‐allocation research findings. 

Conclusions  Several research strategies and specific research topics are suggested for (1) improving the theoretical and methodological basis for detecting possible patient–treatment interactions and (2) stimulating research on major treatment decision needs, such as site, setting, time in treatment (extensiveness and intensity), service components and specific treatment modules. More international research cooperation is needed to clarify the inconsistent findings.
Opiate addiction in China: current situation and treatments
Authors: Tang Yi‐lang , Zhao Dong , Zhao Chengzheng , Cubells Joseph F.
Published: February 2006

Background  Historically, China has had extraordinarily high rates of opiate dependence. These rates declined drastically following the 1949 revolution; however, opiate abuse has re‐emerged in the late 1980's and has spread quickly since then.

Aims  To describe the current situation of opiate addiction and treatments in China and make some suggestions.

Design  A descriptive study based on literature searched from Medline and the China National Knowledge Infrastructure database (1996 to 2004) and hand‐picked references.

Findings  The number of registered addicts in 2004 was 1.14 million (more than 75% of them heroin addicts), but the actual number is probably far higher. Opiate abuse contributes substantially to the spread of HIV/AIDS in China, with intravenous drug use the most prevalent route of transmission (51.2%). Currently, the main treatments for opiate dependence in China include short‐term detoxification with opiate agonists or non‐opiate agents, such as clonidine or lofexidine; Chinese herbal medicine and traditional non‐medication treatments are also used. Methadone maintenance treatment (MMT) has not been officially approved by the Chinese government for widespread implementation, but some pilot studies are currently underway.

Conclusion  China faces substantial drug abuse problems that appear to be worsening with time. Opiate dependence is a major threat to the public health and social security of China because of its devastating medical effects, its impact on risk for HIV/AIDS and criminal behaviors, low rates of recovery and high rates of relapse. There is an urgent need to implement MMT and other modern treatments for opiate dependence more widely in China.
Review article: safe amounts of gluten for patients with wheat allergy or coeliac disease
Authors: HISCHENHUBER C. , CREVEL R. , JARRY B. , MÄKI M. , MONERET‐VAUTRIN D. A. , ROMANO A. , TRONCONE R. , WARD R.
Published: February 2006

For both wheat allergy and coeliac disease the dietary avoidance of wheat and other gluten‐containing cereals is the only effective treatment. Estimation of the maximum tolerated amount of gluten for susceptible individuals would support effective management of their disease.

Literature was reviewed to evaluate whether an upper limit for gluten content in food, which would be safe for sufferers from both diseases, could be identified.

When setting gluten limits for coeliac disease sufferers, the overall potential daily intake should be considered, while for wheat allergy limits should be based on single servings. For coeliac disease sufferers this limit should lie between 10 and 100 mg daily intake. For wheat allergy, lowest eliciting doses for children lie in the lower milligram range, while for adults they are most significantly higher.

Gliadins (part of the gluten proteins) not only trigger coeliac disease, but are also major allergens in wheat allergy. Therefore, measurement of gliadins with validated enzyme‐linked immunosorbent assay methods provides an appropriate marker for assessing gluten and/or wheat protein contents in food. Available data suggest that a maximum gluten content for ‘gluten‐free’ foods could be set, which protects both wheat allergy sufferers and coeliac patients.
Effect of botulinum toxin antral injection on gastric emptying and weight reduction in obese patients: a pilot study
Authors: GUI D. , MINGRONE G. , VALENZA V. , SPADA P. L. , MUTIGNANI M. , RUNFOLA M. , SCARFONE A. , DI MUGNO M. , PANUNZI S.
Published: February 2006

Background  A potential approach to the treatment of morbid obesity is reduction of gastric emptying to achieve satiety. Botulinum toxin A (Btx‐A) is a long‐acting inhibitor of acetylcholine‐mediated peristalsis, which is mainly responsible for gastric motility.

Aim  To investigate whether botulinum toxin A, injected in the antrum of obese patients, delays gastric emptying.

Methods  In a double_blind study, 18 healthy obese subjects (body mass index >30) were randomized into three groups (BTX133, BTX200 and Saline); they received Btx‐A133U, Btx‐A200U, or saline under endoscopic control. Gastric emptying was tested by scintigraphy before and 10 days after treatment. Body weight variations and appetite sensation were recorded after 5 weeks.

Results  Fourteen patients completed the study. The botulinum toxin A‐treated groups showed weight reduction, which was not statistically significant. The effects on gastric emptying were variable. Most of the botulinum toxin A treated patients reported a reduced appetite.

Conclusion  This pilot clinical trial suggests potential activity of botulinum toxin A for the manipulation of appetite.
CDP571, a humanized monoclonal antibody to tumour necrosis factor‐α, for steroid‐dependent Crohn's disease: a randomized, double‐blind, placebo‐controlled trial
Authors: FEAGAN B. G. , SANDBORN W. J. , LICHTENSTEIN G. , RADFORD‐SMITH G. , PATEL J. , INNES A.
Published: February 2006

Background  More than 50% of patients with Crohn's disease become either steroid resistant or dependent. Accordingly, development of new treatments for steroid‐dependent Crohn's disease is a research priority.

Aim  To evaluate CDP571, a humanized antibody to tumour necrosis factor‐α, for the treatment of steroid‐dependent Crohn's disease.

Methods  Patients with steroid‐dependent Crohn's disease (n = 271) were enrolled in a 36‐week, double‐blind, placebo‐controlled trial. Steroid dependence was defined as use of prednisolone or prednisone (15–40 mg/day) or budesonide (9 mg/day) for ≥8 weeks, a previous failed attempt to decrease or discontinue steroids within 8 weeks of screening, and a Crohn's Disease Activity Index score of ≤150 points. Patients were randomized to receive intravenous CDP571 10 mg/kg or placebo 8‐weekly through to week 32. Steroids were then tapered using a defined schedule. The primary efficacy endpoint was the percentage of patients with steroid sparing, defined as discontinuation of steroid therapy without a disease flare (Crohn's Disease Activity Index score ≥220 points) at week 36.

Results  Steroid sparing occurred in 53 of 181 (29.3%) CDP571 patients and 33 of 90 (36.7%) placebo patients (P = 0.24). Adverse events occurred at similar frequencies in both treatment groups.

Conclusions  CDP571 was ineffective for sparing steroids in patients with steroid‐dependent Crohn's disease. CDP571 was well tolerated.
The prevalence of Barrett's oesophagus in a cohort of 1040 Canadian primary care patients with uninvestigated dyspepsia undergoing prompt endoscopy
Authors: VELDHUYZEN VAN ZANTEN S. J. O. , THOMSON A. B. R. , BARKUN A. N. , ARMSTRONG D. , CHIBA N. , WHITE R. J. , ESCOBEDO S. , SINCLAIR P.
Published: February 2006

Background  The prevalence of Barrett's oesophagus in patients undergoing gastroscopy may be influenced by possible referral bias.

Aim  To present the prevalence of Barrett's oesophagus from the the Canadian Adult Dyspepsia Empirical Therapy Prompt Endoscopy study and to explore potential risk factors for its presence.

Methods  Patients had not been on treatment for dyspepsia for 2–4 weeks prior to endoscopy, which was performed within 10 working days of presentation.

Results  Barrett's oesophagus was endoscopically suspected in 53 of 1040 cases (5%) and histologically confirmed by the presence of intestinal metaplasia in 25 (2.4%). The prevalence of biopsy‐proven Barrett's oesophagus was 4% in patients with dominant reflux‐like symptoms. Sixty‐four percent with confirmed Barrett's oesophagus had dominant reflux‐like symptoms compared with 37% without Barrett's oesophagus. Barrett's oesophagus was more common in patients >50 years of age; 68% of cases were males. The mean duration of symptoms was 10 years, yet 16% had symptoms of <1‐year duration. Endoscopic reflux oesophagitis was present in 68% of confirmed Barrett's oesophagus patients.

Conclusions  Barrett's oesophagus is confirmed on biopsy in about half of endoscopically suspected Barrett's oesophagus patients. Barrett's oesophagus is more common in males, in those with dominant reflux‐like symptoms, and in patients with a longer symptom history.
Subacute airway obstruction from a tracheal mucosal flap
Authors: Farr M. J. , Cyna A. M.
Published: February 2006

We report the case of a 15‐year‐old girl with a near fatal obstructive tracheal lesion following tracheal intubation. The patient developed stridor and acute respiratory distress 29 h following tracheal extubation, after 35 h intubation in the intensive care unit. The failure of conventional management of stridor, including re‐intubation, to provide a satisfactory airway prompted an urgent bronchoscopy, which revealed a tracheal mucosal flap causing 80% obstruction of the subglottic trachea. The fibreoptic bronchoscope allowed careful placement of a tracheal tube distal to the obstruction. The patient eventually made a full recovery. The low incidence of similar lesions and the lack of distinguishing clinical features from other causes of post‐extubation stridor make diagnosis and appropriate management of this life‐threatening condition difficult. We discuss how early consideration of the diagnosis and optimal initial management reduce the risk of an adverse outcome.
Incidence and significance of errors in a patient ‘track and trigger’ system during an epidemic of Legionnaires' disease: retrospective casenote analysis
Authors: Smith A. F. , Oakey R. J.
Published: February 2006

Early warning scoring is designed to be an objective tool to aid identification of hospital patients at risk of deterioration. ‘Track and trigger’ systems using such scores are widely used but many aspects of scoring have not been clarified. We aimed to document how observations and scores are used in practice as part of a typical track and trigger system. We extracted patient observations and early warning scores from the casenotes of 189 patients admitted to Furness General Hospital during a large outbreak of Legionnaires' disease in 2002. We used these 3739 sets of primary observations to recalculate scores, and compared them with those recorded in the casenotes. Recording of patient observations was variable. Early warning scores were derived from 2607 sets of observations (69.7%), of which 571 (21.9%) had been incorrectly calculated. Incorrect scoring meant that 66 of 270 patients (24.4%) whose observations should have reached the trigger value did not. Patients with more abnormal observations were more likely to be misscored. Scoring errors were more likely to lead to underscoring as the degree of physiological abnormality increased. Patients with confirmed Legionnaires' disease were more likely to be incorrectly scored. We conclude that the assignment of early warning scores is prone to error and this may delay referral of at‐risk patients for critical care management.
Anaphylaxis to Gelofusine® confirmed by in vitro basophil activation test: a case series*
Authors: Apostolou E. , Deckert K. , Puy R. , Sandrini A. , De Leon M. P. , Douglass J. A. , Rolland J. M. , O'Hehir R. E.
Published: February 2006

The plasma expander Gelofusine® (succinylated gelatin) is a recognised cause of peri‐operative anaphylaxis. Current diagnosis of Gelofusine sensitivity is by skin testing, a procedure that itself carries a risk of allergic reaction. We evaluated the reliability of the in vitro basophil activation test as a diagnostic assay for Gelofusine sensitivity in subjects with a clinical history highly suggestive of Gelofusine allergy. Six patients with peri‐operative anaphylaxis clinically attributed to Gelofusine were skin tested to confirm sensitivity. Control subjects included three healthy subjects and five subjects allergic to a neuromuscular blocking drug, all negative on Gelofusine skin testing. Whole blood basophil activation to Gelofusine was analysed by flow cytometry for CD63 surface expression. All of the Gelofusine sensitive patients and one of the control allergic subjects showed positive basophil activation to Gelofusine. In this series of subjects, the basophil activation test for Gelofusine allergy had a sensitivity of 100% and a specificity of 87.5%. Our findings suggest that basophil activation testing is a safe and reliable in vitro assay for prediction or confirmation of Gelofusine sensitivity in patients with high clinical suspicion of Gelofusine‐induced anaphylaxis.
A CD33‐specific single‐chain immunotoxin mediates potent apoptosis of cultured human myeloid leukaemia cells
Authors: Schwemmlein Michael , Peipp Matthias , Barbin Karin , Saul Domenica , Stockmeyer Bernhard , Repp Roland , Birkmann Josef , Oduncu Fuat , Emmerich Bertold , Fey Georg H.
Published: February 2006

A novel single‐chain immunotoxin was constructed by combining a CD33‐specific single chain Fv (scFv) antibody fragment with an engineered variant of Pseudomonas exotoxin A (ETA). The variant toxin carries the KDEL peptide at its C‐terminus, a cellular peptide mediating improved retrograde transport to the endoplasmic reticulum. The purified recombinant fusion protein induced potent apoptosis of the human myeloid cell lines U937, HL‐60 and THP‐1. Up to 98% of U937 cells were eliminated after treatment for 72 h with a single dose of 500 ng/ml (c. 7 nmol/l). Killing was antigen‐specific and occurred by apoptosis. A control protein, consisting of a CD19‐specific scFv antibody fragment fused to the ETA‐KDEL toxin, failed to induce death of the CD19‐negative cell lines U937, HL‐60 and THP‐1. The CD33‐ETA toxin also mediated apoptosis of fresh patient‐derived acute myeloid leukaemia cells from bone marrow and peripheral blood. The pronounced antigen‐restricted cytotoxicity of the novel fusion protein makes it a candidate for further evaluation of its therapeutic potential.
2D and 3D potential‐field upward continuation using splines
Authors: Wang Bingzhu
Published: February 2006

The dominant upward‐continuation technique used in the potential‐field geophysics industry is the fast Fourier transform (FFT) technique. However, the spline‐based upward‐continuation technique presented in this paper has some advantages over the FFT technique. The spline technique can be used to carry out level‐to‐uneven surface 2D and 3D potential‐field upward continuation. An example of level‐to‐uneven surface upward continuation of 3D magnetic data using the spline technique is shown, and it is evident that the continued anomalies are very close to the theoretical values. The spacing can be irregular. Synthetic examples using the spline technique to continue noise‐contaminated gravity and magnetic data upward to an altitude of 15 km on irregular grids are shown. Gaussian noise with a zero mean and a standard deviation of 1% does not cause much error and can readily be tolerated. Through comparison with the FFT technique, it is found that for low‐altitude gravity and magnetic upward continuation, both the FFT technique and the spline technique are suitable; for high‐altitude upward continuation, the FFT technique is inaccurate, whereas the spline technique works very well. Also, upward continuation by the spline technique has a smaller edge effect than upward continuation by the FFT technique. The spline‐based upward continuation technique works fairly well even when the periphery of a grid is not quiet: it is rather robust in general. A real example shows that the spline technique can be employed to perform upward continuation of total‐field magnetic data and to de‐emphasize near‐surface noise.
Diptericin expression in bacteria infected Drosophila mbn‐2 cells – effect of infection dose and phagocytosis
Authors: Johansson K. C. , Söderhäll K. , Cerenius L.
Published: February 2006

Drosophila haemocytes play a key role in defence against microbial aggression. Their capacity to sense and dispose of bacteria and also to signal to other immune tissues is probably vital to overcome an infection. In this work we used the haemocyte‐like mbn‐2 cell line to investigate how expression of the antimicrobial peptide diptericin is affected after a high dose bacterial challenge with diaminopimelic acid (DAP)‐peptidoglycan Gram‐positive and Gram‐negative bacteria. We report that diptericin expression is negatively affected by high infection dose and rapid bacterial growth regardless of the type of infection and bacterial virulence and occurs in the absence of mbn‐2 cell death. Furthermore we show that the mbn‐2 cell population is heterogeneous, containing both phagocytic and nonphagocytic cells and that contact with large numbers of bacteria decreases diptericin expression in the phagocytic cell population.
Genome‐wide analysis of gene expression in adult Anopheles gambiae
Authors: Marinotti O. , Calvo E. , Nguyen Q. K. , Dissanayake S. , Ribeiro J. M. C. , James A. A.
Published: February 2006

With their genome sequenced, Anopheles gambiae mosquitoes now serve as a powerful tool for basic research in comparative, evolutionary and developmental biology. The knowledge generated by these studies is expected to reveal molecular targets for novel vector control and pathogen transmission blocking strategies. Comparisons of gene‐expression profiles between adult male and nonblood‐fed female Anopheles gambiae mosquitoes revealed that roughly 22% of the genes showed sex‐dependent regulation. Blood‐fed females switch the majority of their metabolism to blood digestion and egg formation within 3 h after the meal is ingested, in detriment to other activities such as flight and response to environment stimuli. Changes in gene expression are most evident during the first, second and third days after a blood meal, when as many as 50% of all genes showed significant variation in transcript accumulation. After laying the first cluster of eggs (between 72 and 96 h after the blood meal), mosquitoes return to a nongonotrophic stage, similar but not identical to that of 3‐day‐old nonblood‐fed females. Ageing and/or the nutritional state of mosquitoes at 15 days after a blood meal is reflected by the down‐regulation of ∼5% of all genes. A full description of the large number of genes regulated at each analysed time point and each biochemical pathway or biological processes in which they are involved is not possible within the scope of this contribution. Therefore, we present descriptions of groups of genes displaying major differences in transcript accumulation during the adult mosquito life. However, a publicly available searchable database (http://www.angagepuci.bio.uci.edu/) has been made available so that detailed analyses of specific groups of genes based on their descriptions, functions or levels of gene expression variation can be performed by interested investigators according to their needs.