bluuebunny/crossref_metadata_2025 huggingface dataset:
A structured approach to automated testing
Authors: Franceschini Fiorenzo
Published: September 2004

Discusses the problems of how to structure a computerized
process‐oriented test facility [TF] with particular regard to the
aerospace, automotive, electronic, chemical and railway industries and the
military. Covers the areas of test facility functional architecture,
operation philosophy, test plan preparation, data management support, system
access and security, system engineering support, the conducting of the test
and system maintenance support. Concludes that the aim of a structural
approach has been to focalize in an organized framework the attention of a
test‐designer to the operating and supporting functions of a test
facility. The general methodology proposed can be utilised as a reference in
many application fields from defence to commercial systems.
Optimaster robot guidance system
Authors: Wallster Ola
Published: September 2004

Describes a camera‐based sensor system used for robot guidance
systems for application in areas such as small‐batch parts handling,
high‐precision assembly and 3D assembly of parts. Outlines the
production steps performed by robots from parts handling, depalletization,
unloading from conveyors, assembly operating and inspection. Explains how the
vision system is fully integrated in the robot and looks at its hardware,
software and technical specifications. Concludes that the system is
multifunctional and due to its robust construction is suitable for use in
hostile industrial environments.
Novel catalytic gas sensor has long‐life and low power
consumption
Authors: Lei Yuanjin , Jiang Zhufeng , Tao Yuemei , Wu Zhinhong
Published: September 2004

Describes a new catalytic gas sensor which claims high stability and
low‐consumed power by using extra fine wires of precious metals and the
addition of a support stabilizer and pore‐making agents. Outlines the
experiment methods and materials used, the principles of detection and the
performance of the catalytic elements. Concludes that with the addition of a
support stabilizer which makes the specific surface of the support decrease
slowly during use, and a pore‐making agent which can eliminate the
effect of the internal diffusion on the sensor, the novel catalytic sensor
can be widely applied to the detection of damp gas in coal mines and various
combustible gases on the earth’s surfaces.
RFID enhances materials handling
Authors: Ollivier Michael
Published: September 2004

Describes developments in radio frequency identification [RFID]
techniques, using examples from existing applications in the motor industry,
breweries and mail order companies. Looks at the miniaturization resulting
from integrated circuit technology, the advantages of passive transponders
and one of the latest versions of transponder, the Multipage [M/P], a tag
which contains the equivalent of 17 individual transponders in a single unit.
Concludes that the advent of low‐cost integrated RFID technology has
enabled new solutions to production problems in the materials handling
environment. Tagging brings improvements in efficiency, security and
accuracy by uniquely labelling units with the production process.
Customer‐centred growth: five strategies for building competitive advantage
Authors: Whiteley Richard , Hessan Diane
Published: September 2004

Suggests that companies can become customer centred by adopting five strategies: shift to a laser‐beam focus; hardwire the voice of the customer; universal collaboration; lasting customer enthusiasm rather than customer satisfaction, and a move to contact leadership.
Is Europe embracing the “interactive age”?
Authors: Sheikh Haaris
Published: September 2004

Considers the transition from the communication age to the “interactive age” through demonstrating Europe’s effort in establishing a network of multimedia information demonstration and support (MI‐DAS‐NET) nodes through the Info2000 initiative.
Developing an internal auditing department balanced scorecard
Authors: Ziegenfuss Douglas E.
Published: September 2004

This article demonstrates the use of the “Balanced Scorecard” methodology developed by Kaplan and Norton in selecting performance measures for internal auditing departments. It then describes: professional standards and guidance concerning the use of performance measures and benchmarking; the “Balanced Scorecard” methodology; and a comprehensive example. Finally, this article concludes with specific recommendations concerning the use of performance measures.
Work in 2020
Authors: Furnham Adrian
Published: September 2004

This article has three themes. First it considers the reflections of those scholars who document current changes in the world‐of‐work and the academic and managerial challenges that these provide. Second, various speculations about the future of work are reviewed including those made 20 years ago attempting to predict the current state of work and those futurological forecasts made at the moment for the world in 20 years time. Finally, two topics are considered in depth – the psychology of unemployment and the experience of teleworking – to illustrate some of the costs and benefits in the new world of work.
Isobolographic and Subthreshold Analysis of Interactions among Felbamate and Four Conventional Antiepileptic Drugs in Pentylenetetrazole‐induced Seizures in Mice
Authors: Borowicz Kinga K. , Luszczki Jarogniew J. , Czuczwar Stanislaw J.
Published: September 2004

Summary:  Purpose: Despite possibility of idiosyncratic reaction development, felbamate (FBM) is recommended in Lennox–Gastaut syndrome and partial refractory epilepsy. The aim of this study was to evaluate the profile of interactions between FBM and four conventional antiepileptic drugs (AEDs): clonazepam (CZP), ethosuximide (ESM), phenobarbital (PB), and valproate (VPA), in pentylenetetrazole (PTZ)‐induced convulsions in mice, a model of myoclonic seizures in humans.

Methods: Data obtained from PTZ‐evoked seizures were compared by use of two basic procedures, the subthreshold method and isobolographic analysis. Results of the chimney test (evaluating motor coordination) also were elaborated isobolographically. Thus it was possible to determine both median toxic dose (TD50) and protective index (PI) for each drug combination.

Results: FBM reduced the clonic seizure activity [with an ED50 of 9.7 mg/kg; TD50, 439.1 mg/kg; and PI, 45.3]. FBM at the dose of 10 mg/kg, but not 7.5 mg/kg, significantly reduced PTZ‐induced convulsions in mice. In the subthreshold method, FBM (7.5 mg/kg) did not affect the protective activity of conventional AEDs used in the study. However, when applied at 10 mg/kg, it enhanced the protective activity of PB and ESM, but not that of VPA or CZP. The nature of these interactions could not be precisely estimated with this method. The exact profile of drug interactions was determined with the use of isobolography. In terms of seizure inhibition, antagonism was found between FBM and VPA applied at the fixed‐dose ratio of 3:1. Synergy was detected between FBM and PB (1:3). Combinations of FBM with VPA (1:3, 1:1), PB (1:1, 3:1), and ESM or CZP (1:3, 1:1, 3:1) led to additive interactions. As regards motor impairment, the combinations of FBM with VPA (1:3) or CZP (1:1, 3:1) were synergistic. Remaining combinations exhibited pure additivity. Pharmacokinetic events may influence FBM/ESM and FBM/CZP interactions, because FBM lowered the brain concentration of ESM and increased that of CZP.

Conclusions: The profitable benefit index was found only for the combination of FBM with PB (1:3). Conversely, the combinations of FBM with either VPA (1:3) or CZP (1:1, 3:1) do not seem promising for the therapy of refractory myoclonic convulsions. Isobolographic analysis provides more reliable clues to be considered by the clinicians willing to introduce AED combinations for the therapy of epilepsy.
Selective Antiepileptic Effects ofN‐Palmitoylethanolamide, a Putative Endocannabinoid
Authors: Sheerin Aaron H. , Zhang Xia , Saucier Deborah M. , Corcoran Michael E.
Published: September 2004

Summary: Purpose:The purpose of this study was to determine whetherN‐palmitoylethanolamide (PEA), a putative endocannabinoid, would be effective against kindled amygdaloid seizures. For a comparison with earlier work, we also tested the effectiveness of PEA against pentylenetetrazol (PTZ)‐induced convulsions.

Methods:Kindling electrodes were implanted bilaterally in the amygdala in 32 Long‐Evans rats. After the kindling of generalized (stage 5) seizures, the effects of PEA administration [i.p.; 1, 10, 100 mg/kg in dimethylsulfoxide (DMSO)] were evaluated for anticonvulsant activity. PEA (40 mg/kg, i.p. in DMSO) also was tested for anticonvulsant activity against PTZ‐induced convulsions (75 mg/kg, i.p.).

Results:After i.p. administration of PEA, kindled rats displayed an increased latency to clonus at the 1‐mg/kg dose. No other dose‐dependent effects were noted. When tested against PTZ‐induced convulsions, PEA protected against tonic convulsions and prolonged the latency between convulsive episodes.

Conclusions:PEA produces antiepileptic effects, but does not completely suppress seizures. The mechanism of action of PEA remains to be defined.
Successful Management of Intractable Epilepsy with Lidocaine Tapes and Continuous Subcutaneous Lidocaine Infusion
Authors: Mori Kenji , Ito Hiromichi , Toda Yoshihiro , Hashimoto Toshiaki , Miyazaki Masahito , Saijo Takahiko , Kuroda Yasuhiro
Published: September 2004

Summary:  Purpose: We report the successful management of a 10‐year‐old girl with intractable frontal lobe epilepsy by using lidocaine tapes and continuous subcutaneous lidocaine infusion.

Methods: This patient's seizures were refractory to conventional antiepileptic drugs (AEDs) and mexiletine, but they responded well to the intravenous infusion of lidocaine. The intravenous infusion of lidocaine was replaced by lidocaine tape therapy, and subsequently by continuous subcutaneous lidocaine infusion therapy. The lidocaine tape (Penles, Nihon Lederle, Tokyo Japan) used was a stamp‐sized (30.5 × 50.0 mm) tape containing 18 mg of lidocaine. We used 25 lidocaine tapes every 12 h (50 tapes/day). Lidocaine hydrochloride (10%) was administered continuously at a dose of 1.5 mg/kg/h (0.3 ml/hour) through a 27‐G needle that was inserted in the subcutaneous tissue.

Results: Lidocaine tape therapy showed good efficacy for 1 year. After that, six lidocaine tapes were added 6 h after the exchange of 25 lidocaine tapes [62 tapes/day (25,6,25,6)], because the seizures became frequent when the lidocaine tapes were being exchanged. The seizures were then well controlled, but dermatitis due to the lidocaine tapes grew serious, and lidocaine tape therapy had to be stopped. Continuous subcutaneous infusion of lidocaine applied in place of lidocaine tapes provided long‐term seizure control without remarkable side effects.

Conclusions: Lidocaine tape therapy and continuous subcutaneous lidocaine infusion therapy were considered to be useful for controlling this patient's seizures. This is the first report to describe the efficacy of continuous subcutaneous lidocaine infusion therapy for epilepsy.
Mitochondrial Dysfunction and Ultrastructural Damage in the Hippocampus during Kainic Acid–induced Status Epilepticus in the Rat
Authors: Chuang Yao‐Chung , Chang Alice Y. W. , Lin Jui‐Wei , Hsu Shih‐Pin , Chan Samuel H. H.
Published: September 2004

Summary:  Purpose: Prolonged and continuous epileptic seizure (status epilepticus) results in cellular changes that lead to neuronal damage. We investigated whether these cellular changes entail mitochondrial dysfunction and ultrastructural damage in the hippocampus, by using a kainic acid (KA)‐induced experimental status epilepticus model.

Methods: In Sprague–Dawley rats maintained under chloral hydrate anesthesia, KA (0.5 nmol) was microinjected unilaterally into the CA3 subfield of the hippocampus to induce seizure‐like hippocampal EEG activity. The activity of key mitochondrial respiratory chain enzymes in the dentate gyrus (DG), or CA1 or CA3 subfield of the hippocampus was measured 30 or 180 min after application of KA. Ultrastructure of mitochondria in those three hippocampal subfields during KA‐induced status epilepticus also was examined with electron microscopy.

Results: Microinjection of KA into the CA3 subfield of the hippocampus elicited progressive build‐up of seizure‐like hippocampal EEG activity. Enzyme assay revealed significant depression of the activity of nicotinamide adenine dinucleotide cytochrome c reductase (marker for Complexes I+III) in the DG, or CA1 or CA3 subfields 180 min after KA‐elicited temporal lobe status epilepticus. Conversely, the activities of succinate cytochrome c reductase (marker for Complexes II+III) and cytochrome c oxidase (marker for Complex IV) remained unaltered. Discernible mitochondrial ultrastructural damage, varying from swelling to disruption of membrane integrity, also was observed in the hippocampus 180 min after hippocampal application of KA.

Conclusions: Our results demonstrated that dysfunction of Complex I respiratory chain enzyme and mitochondrial ultrastructural damage in the hippocampus are associated with prolonged seizure during experimental temporal lobe status epilepticus.
Epilepsy and Synaptic Reorganization in a Perinatal Rat Model of Hypoxia–Ischemia
Authors: Williams Philip A. , Dou Ping , Dudek F. Edward
Published: September 2004

Summary:  Purpose: One of the potential consequences of perinatal hypoxia–ischemia (H‐I) is the development of epilepsy, and synaptic reorganization in the hippocampus has been associated with epilepsy after an injury. We tested the hypothesis that perinatal H‐I will induce spontaneous motor seizures, hippocampal lesions, and synaptic reorganization in the dentate gyrus.

Methods: The right common carotid artery of 7‐day‐old rats was permanently ligated, and the rats were placed for 120 min into a chamber filled with 8% oxygen (37°C). Animals were directly observed for chronic motor seizures for 7 to 24 months after the H‐I insult.

Results: Nearly half of the rats (i.e., eight of 20) were seen to have spontaneous motor seizures after the H‐I injury. The ipsilateral hippocampi from both the rats with seizures and the rats not seen to have seizures had hippocampal lesions and increased amounts of Timm stain in the inner molecular layer (IML) compared with controls. The contralateral hippocampi from the rats with seizures, but not the hippocampi from the rats not seen to have seizures, had significantly increased amounts of Timm stain in the IML.

Conclusions: These results suggest that perinatal H‐I can induce epilepsy, ipsilateral hippocampal lesions, and mossy fiber sprouting in the lesioned and contralateral hippocampus.
Aging Alters Electroencephalographic and Clinical Manifestations of Kainate‐induced Status Epilepticus
Authors: Darbin Olivier , Naritoku Dean , Patrylo Peter R.
Published: September 2004

Summary:  Purpose: The elderly exhibit an increased risk for developing status epilepticus and status‐related morbidity and mortality. However, it is unclear how aging alters the progression of electroencephalographic (EEG) activity and behavioral manifestations during status epilepticus.

Methods: A repetitive low‐dose kainate treatment protocol (2.5 mg/kg/h; i.p.) was used in this study in conjunction with EEG and behavioral monitoring from freely behaving adult (7–8 months) and aged (22–25 months) Fischer 344 rats to assess the effects of aging on status epilepticus.

Results: During kainate treatment, both groups exhibited an increase in EEG power that corresponded with the time course of kainate treatment. However, visual inspection and spectral analysis revealed a reduction of the faster frequencies (12.5–35 Hz) in the EEGs of aged rodents. A similar progression of behavioral manifestations was observed in adult and aged rodents during kainate treatment, although the frequency of preseizure manifestations (e.g., wet‐dog shakes; aged rats, 110 events/h vs. adults, 25 events/h; median values) was greater, and latency to onset for any given behavioral manifestation (e.g., class V seizures; aged median, 60 min, vs. adult median, 145 min) was consistently shorter within the aged group.

Conclusions: These data reveal that aged Fischer 344 rats exhibit altered EEG activity (reduction of higher frequencies) and clinical manifestations during kainate‐induced status epilepticus. Taken together, these data indicate an age‐related change in seizure onset and spread after exposure to glutamate analogues.
Reviews: Use of Insulin and Oral Hypoglycemic Medications in Patients with Diabetes Mellitus and Advanced Kidney Disease
Authors: Snyder Richard W. , Berns Jeffrey S.
Published: September 2004

Diabetes mellitus is recognized as a leading cause of chronic kidney disease (CKD) and end‐stage renal disease (ESRD) in the United States. There is a vast array of medications used to treat diabetes, including insulin and the sulfonylureas, as well as newer classes of drugs such as the thiazolidinediones and biguanides. In patients with reduced glomerular filtration rate (GFR), it is necessary to decrease the dosage of some of these drugs, while others are best avoided altogether. Accumulation of either the parent compound or its metabolites can result in symptomatic hypoglycemia, or in the case of metformin, significant lactic acidosis. In this article we will review the use of insulin and the various classes of oral medications used to treat type 2 diabetes mellitus, focusing on their pharmacokinetic properties and dosing in patients with advanced kidney disease.
K/DOQI Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease Patients: Some Therapeutic Implications
Authors: Uribarri Jaime
Published: September 2004

The National Kidney Foundation (NKF) has recently published clinical practice guidelines for bone metabolism and disease in chronic kidney disease (CKD) patients (the Kidney Disease Outcomes Quality Initiative [K/DOQI]). Data from the literature show that the majority of dialysis patients treated with traditional calcium‐containing phosphorus binders and vitamin D or vitamin D analogue preparations have serum parathyroid hormone (PTH), calcium, and phosphorus levels outside these strict K/DOQI target ranges. In fact, it appears that achieving and maintaining the targets values set by these guidelines is virtually impossible without the simultaneous use of the new calcimimetic agents and non‐calcium‐containing binders, agents that have significant cost barriers to their use in many patients. These guidelines are welcome, but they may be impractical for the majority of dialysis patients. The impact of these guidelines in improving the parameters of bone metabolism and disease among dialysis patients remains to be determined.
American Society of Diagnostic and Interventional Nephrology Section Editor: Stephen Ash: Percutaneous Technique of Presternal Peritoneal Dialysis Catheter Placement
Authors: Sreenarasimhaiah Vijay P. , Margassery Suresh K. , Martin Kevin J. , Bander Steven J.
Published: September 2004

Presternally exiting peritoneal dialysis (PD) catheters have been described as advantageous compared to abdominally exiting catheters with regard to infection, wound healing, and other complications. Placement of such catheters has only been described with open surgical techniques and not by percutaneous means. In this article we describe 15 patients who received percutaneously placed PD catheters with a presternal exit site. These patients received their procedures in an outpatient procedure room performed by an interventional nephrologist. In all but one case, immediate technical success was achieved. In only one case was peritonitis documented. All catheters are still functional, including some with follow‐up as long as 15 months. Percutaneous placement of presternally exiting PD catheters is technically straightforward and can avoid an open surgical procedure.
Editorials: Antioxidant Therapy in Uremia: Evidence‐Based Medicine?
Authors: Gordon Carrie A. , Himmelfarb Jonathan
Published: September 2004

Because of correlations between cardiovascular disease, inflammation, and renal failure, many investigators are pursuing nontraditional risk factors and therapies in order to reduce cardiovascular morbidity and mortality in the end‐stage renal disease (ESRD) population. Despite the disappointing lack of clinical effects with antioxidative therapies seen in large studies of the general population, some studies suggest a diminished cardiovascular risk in individuals with renal failure. This expanding new line of evidence is promising as a method to help alleviate the more than 20‐fold increase in risk of cardiovascular events in the ESRD population. Most of the current available studies have evaluated laboratory or physiologic endpoints, such as endothelial function and measures of oxidative burden, and have evaluated relatively small numbers of patients. However, it is currently premature to initiate widespread clinical therapy with antioxidants. Further investigation in this area should be supported to see if reported benefits can be duplicated in more widespread study populations, and to more accurately define the most appropriate choice of therapy, mode of therapy, and dose.
Serum Ferritin in Chronic Kidney Disease: Reconsidering the Upper Limit for Iron Treatment
Authors: Fishbane Steven , Kalantar‐Zadeh Kamyar , Nissenson Allen R.
Published: September 2004

Intravenous iron treatment in hemodialysis patients improves the response to recombinant human erythropoietin (rHuEPO) and facilitates achievement of targets for hemoglobin and hematocrit. Excessive treatment, however, could expose patients to risks related to iron overload and oxidative stress. Therefore international treatment guidelines generally recommend that intravenous iron be discontinued when serum ferritin is greater than 500–1000 ng/ml. In this article we explore the relevant issues that inform the decisions as to what levels of serum ferritin are used as the upper limit for treatment. We conclude that the current published literature is inadequate for developing evidence‐based guidelines. Clinical judgment is critical to properly weigh the risks and benefits of intravenous iron treatment in the context of the individual patient.
Peritoneal Dialysis International: Its Origins and Impact
Authors: Oreopoulos Dimitrios G.
Published: September 2004

Peritoneal Dialysis International (PDI) started in 1988 as a four‐page document (Peritoneal Dialysis Bulletin) intended to inform all those who visited the Toronto Western Hospital peritoneal dialysis unit about advances in peritoneal dialysis. Soon it became a journal distributed free of charge to 13,000 individuals. Subsequently it became the official publication of the International Society for Peritoneal Dialysis. For many years it was the main forum for publication of the best articles in peritoneal dialysis. As a result, in 1997, its “impact factor” increased to 2.129, putting it in fourth position among the nephrology journals. PDI greatly stimulated the expansion of peritoneal dialysis in the 1980s and 1990s, and remains the main source of knowledge on clinical and investigative aspects of peritoneal dialysis.
Phylogeny of the superfamily Gelechioidea (Lepidoptera: Ditrysia): an exemplar approach
Authors: Kaila Lauri
Published: September 2004

Phylogenetic relationships within the megadiverse lepidopteran superfamily Gelechioidea have been poorly understood and consequently the family level classification has been problematic. An analysis of phylogeny using 193 characters, including 241 informative character states, derived from larval, pupal and adult morphology and larval ecology, was performed to resolve the phylogeny of the Gelechioidea. 143 species representing the diversity of the putative Gelechioidea were included, supplemented with 13 species representing 11 other Ditrysian families. The monophyly of the Gelechioidea was supported, although only with homoplastic characters. The putative position of the Gelechioidea as the sister group of the Apoditrysia was not supported, since the Gelechioidea was nested within this clade. The Gelechioidea was divided into two main lineages: (1) the gelechiid lineage constituting Deoclonidae, Syringopainae, a re‐composed Coleophoridae (including Coelopoetinae and Batrachedrinae as paraphyletic with Stathmopodinae, and Coleophorinae nested within it), Momphidae, Pterolonchidae, Scythrididae, Cosmopterigidae, and Gelechiidae, and (2) the oecophorid lineage constituting the “autostichid” family assemblage (including taxa formerly assigned to Autostichinae, Holcopogoninae, Symmocinae, Glyphidoceridae and Lecithoceridae), Xyloryctidae s.l. (including a paraphyletic Xyloryctidae of authors, some oecophorids of authors, Deuterogoniinae and Blastobasinae), Oecophoridae s.s., Amphisbatidae s.s., Carcinidae, Stenomati[n/d]ae, Chimabachidae and Elachistidae (including Depressariinae s.s., Telechrysis, Ethmiinae, Hypertrophinae s.l., miscellaneous “amphisbatids”sensu authors, Aeolanthinae, Parametriotinae, Agonoxeninae and Elachistinae). Detritivory/fungivory may have evolved only twice within Gelechioidea, though the evolution of larval food substrate use frequently reverses. To avoid an unnecessary further proliferation of names, it is recommended that no further family group names are introduced within the Gelechioidea, unless based on a rigorous analysis of inter‐relationships.
Escaping the matrix: a new algorithm for phylogenetic comparative studies of co‐evolution
Authors: Wojcicki Maggie , Brooks Daniel R.
Published: September 2004

An algorithm for generating host cladograms from parasite‐host cladograms derived from parasite phylogenies, Phylogenetic Analysis for Comparing Trees (PACT), is described. PACT satisfies Assumption 0, that all the information in each parasite‐host cladogram must be used in a co‐evolutionary analysis, and that the host relationships depicted in the final host cladogram must be logically consistent with the phylogenetic relationships depicted in every part of every parasite‐host cladogram used to construct the host cladogram. It accounts for cases of speciation by host switching and expansion of host range, and reticulated host relationships, in addition to co‐speciation, sympatric speciation, and extinction in all input parasite‐host cladograms, and does so withouta prioriweighting schemes and withouta posteriorimanipulation of the data.
Review article: trials on reflux disease — the role of acid secretion and inhibition
Authors: Sonnenberg A.
Published: September 2004

The importance of gastric acid in the pathophysiology of gastro‐oesophageal reflux disease is substantiated by the extraordinary therapeutic success of acid inhibition in the management of the disease. The influence of many risk factors for gastro‐oesophageal reflux disease is also mediated through their effect on gastric acid secretion and acid reflux.Helicobacter pylorireduces the risk of gastro‐oesophageal reflux disease by causing corpus gastritis and reducing gastric acid output. The geographical and temporal trends ofH. pyloriinfection in human populations and its influence on gastric acid secretion are responsible for much of the apparent epidemiology of gastro‐oesophageal reflux disease.

On average, intra‐oesophageal exposure to acid is higher in patients who respond poorly to antisecretory medication. It also tends to increase with increasing severity of reflux disease. However, gastric acid secretion and intra‐oesophageal acid exposure vary markedly in reflux patients. The degrees of gastric or intra‐oesophageal acidity do not allow the prediction of the presence or severity of gastro‐oesophageal reflux disease in the individual subject. The many clinical trials on gastro‐oesophageal reflux disease indicate that the reflux of gastric acid constitutes an essential mechanism in the development of this disease, but that additional and partly unknown risk factors must contribute to its aetiology and promote its occurrence in the individual patient.
Review article: towards consistency in the endoscopic diagnosis of Barrett's oesophagus and columnar metaplasia
Authors: Armstrong D.
Published: September 2004

Barrett's oesophagus is associated with severe reflux disease and is a risk factor for oesophageal adenocarcinoma. However, there is a lack of consensus on how to assess the presence and extent of Barrett's oesophagus in clinical practice. A diagnosis of Barrett's oesophagus is currently based on the recognition of an abnormal oesophageal mucosa at endoscopy. However, a diagnosis cannot be made solely on this basis, and a true diagnosis requires the identification of an area suspicious for columnar metaplasia at endoscopy, followed by histological confirmation.

Currently, difficulties in the assessment of Barrett's oesophagus include a lack of consistent definitions of endoscopic landmarks (such as the gastro‐oesophageal and squamo‐columnar junctions), a lack of standardization of descriptions of the extent of Barrett's oesophagus, and limited communication between the endoscopist and the pathologist, which hampers accurate histological confirmation. It is therefore important to develop an endoscopic description of Barrett's oesophagus, with a clear definition of endoscopic landmarks, to determine, amongst other things, whether anti‐reflux therapy produces regression or a reduction in the length of Barrett's oesophagus.

With this background, a subgroup of the International Working Group on the Classification of Oesophagitis was charged with developing a simple, practicable classification system, suitable for use with standard endoscopes, which would be easy to apply in clinical practice and in large clinical studies. Described in this review are a series of propositions and an overview of the ‘CM classification’, developed by the International Working Group on the Classification of Oesophagitis, to facilitate the endoscopic description of Barrett's oesophagus. It is hoped that these propositions will be the first step in the development of standard endoscopic diagnostic criteria for Barrett's oesophagus, relevant to clinical practice and clinical research.
Review article: emerging techniques for screening and surveillance in Barrett's oesophagus
Authors: Sharma P.
Published: September 2004

The incidence of oesophageal adenocarcinoma continues to increase in the US and the Western world, with the 5‐year survival rate for this cancer still being very dismal.

The diagnosis of Barrett's metaplasia and dysplasia (i.e. screening and surveillance) currently requires endoscopy with biopsy of the abnormally appearing distal oesophagus. Surveillance endoscopy in patients with Barrett's oesophagus relies on the performance of random biopsies from the metaplastic segment, with the aim of identifying dysplasia and/or cancer. However, intestinal metaplasia and dysplasia are not uniformly distributed within the columnar‐lined mucosa in the distal oesophagus, and the sensitivity of standard endoscopy with biopsy for the detection of these lesions is low.

New techniques to improve the accuracy of endoscopic diagnosis, as well as to identify patients at high risk for neoplasia development, have recently been developed and most are currently being evaluated in clinical studies. The results with these techniques, although promising, are still preliminary. They hold promise for the improved detection of dysplasia and neoplasia at an early stage of development, with a greater chance for early treatment, and therefore a greater likelihood of either cure of adenocarcinoma or prevention of its development from dysplasia.
Review article: prevalence of Barrett's oesophagus and metaplasia at the gastro‐oesophageal junction
Authors: Sharma P.
Published: September 2004

Barrett's oesophagus, a complication of chronic gastro‐oesophageal reflux disease, is the premalignant lesion for oesophageal and gastro‐oesophageal junction adenocarcinoma. Described in the 1950s by Norman Barrett, the diagnostic criterion for this lesion has evolved significantly over the last three decades. Endoscopic Barrett's oesophagus requires the recognition of columnar mucosa in the distal oesophagus; documentation of metaplastic tissue is confirmed by random biopsies. Given this changing definition of Barrett's metaplasia, the prevalence rates vary in the literature depending on the diagnostic criteria applied. However, it is generally accepted that approximately 10% of patients with chronic gastro‐oesophageal reflux disease will be diagnosed with this condition. There are no population‐based studies on the prevalence of Barrett's oesophagus, but emerging data indicate that it may be equally prevalent in asymptomatic individuals. These studies require confirmation. Although the incidence of oesophageal adenocarcinoma is increasing rapidly, it is unclear whether the true incidence of Barrett's oesophagus is increasing at the same time. On the other hand, metaplasia at the gastro‐oesophageal junction appears to be distinct from Barrett's oesophagus, is probably not related to chronic gastro‐oesophageal reflux disease and is a common finding if routine biopsies are obtained at the gastro‐oesophageal junction. This article reviews our current understanding of the diagnosis, definition and prevalence of both of these lesions.
Review article: what I do now to manage adenocarcinoma risk, and what I may be doing in 10 years' time
Authors: Spechler S. J.
Published: September 2004

This article summarizes the present recommendations for the screening, surveillance and treatment of Barrett's oesophagus, and identifies those areas in which change seems likely within the next decade. As a result of economic constraints and emerging data on ethnic variations in the frequency of Barrett's oesophagus, future screening programmes will probably focus on those individuals most likely to develop Barrett's adenocarcinomas: older white men whose gastro‐oesophageal reflux symptoms are of long duration. The present surveillance strategy for patients with Barrett's oesophagus relies heavily on random biopsy sampling of the oesophagus to find dysplasia. In the future, biomarkers other than dysplasia may be used to identify patients at high risk for carcinogenesis, and physicians may use endoscopic techniques, such as fluorescence spectroscopy, to identify areas of dysplasia for biopsy sampling. Indirect evidence suggests that super‐aggressive antisecretory therapy and treatment with non‐steroidal anti‐inflammatory drugs may reduce the risk of cancer in Barrett's oesophagus. Well‐designed prospective studies will be needed to determine whether these treatments have sufficient efficacy in cancer prophylaxis to justify the large numbers needed to treat. Finally, recent data are reviewed, which suggest that the gastro‐oesophageal junction is exposed repeatedly to concentrated acid and to potentially genotoxic concentrations of nitric oxide generated from dietary nitrate. Future studies on carcinogenesis in Barrett's oesophagus may well focus on the combined roles of nitric oxide and gastric acid.
Recognition of iron‐free siderophores by TonB‐dependent iron transporters
Authors: Schalk Isabelle J. , Yue Wyatt W. , Buchanan Susan K.
Published: September 2004

TonB‐dependent iron transporters reside in the outer membranes of Gram‐negative bacteria, transporting ferric‐complexes into the periplasm by a mechanism requiring proton motive force and an integral inner membrane complex, TonB–ExbB–ExbD. Certain TonB‐dependent transporters contain an additional domain at the N‐terminus, which interacts with an inner membrane regulatory protein and a cytoplasmic sigma factor to induce transcription of iron transport genes when a ferric‐ligand is bound at the extracellular surface of the transporter. Transport of the ferric‐ligand is apparently not necessary for transcription induction. Recent biophysical and crystallographic experiments have shown that this subclass of TonB‐dependent iron transporters can bind iron‐free ligands, whereas only the ferric‐ligands are transported into the periplasm. This review focuses on the ligand binding properties of these transporters and includes a discussion of the biological function of the additional domain, the mechanism of transcription induction and the mechanism of ferric‐ligand transport.
Novel substitutions in the σ54‐dependent activator DctD that increase dependence on upstream activation sequences or uncouple ATP hydrolysis from transcriptional activation
Authors: Xu Hao , Kelly Mary T. , Nixon B. Tracy , Hoover Timothy R.
Published: September 2004

Sinorhizobium meliloti DctD is an activator of σ54‐RNA polymerase holoenzyme and member of the AAA+ superfamily of ATPases. DctD uses energy released from ATP hydrolysis to stimulate the isomerization of a closed promoter complex to an open complex. DctD binds to upstream activation sequences (UAS) and contacts the closed complex through DNA looping to activate transcription, but the UAS is not essential for activation if DctD is expressed at higher than normal levels. Introduction of specific substitutions within or near the conserved ESELFG motif in the C3 region of a truncated, constitutively active form of DctD produced several mutant forms of the protein that had increased dependence on the UAS for activation. Removing the DNA‐binding domain from one UAS‐dependent mutant and from one activation‐deficient mutant significantly increased transcriptional activation, indicating that the DNA‐binding domain interfered with the activities of these mutant proteins. A UAS‐dependent mutant with a P315L substitution in the C6 region was identified from a genetic screen. Alanine scanning mutagenesis of conserved amino acid residues around Pro‐315 produced two additional UAS‐dependent mutants as well as several mutants that failed to activate transcription but retained ATPase activity. In contrast to the two mutant proteins with substitutions in the C3 region, removal of the DNA‐binding domain from the mutant proteins with substitutions in the C6 region did not stimulate their activity. The residues in the C6 region that were altered are in a probable hinge region between the α/β and α‐helical subdomains of the AAA+ domain. The α‐helical subdomain contains the sensor II helix that has been implicated in other AAA+ proteins as sensing changes in the nucleotide during the hydrolysis cycle. Substitutions in the hinge region may have abolished nucleotide sensing by interfering with subdomain interactions, altering the relative orientation of the sensor II helix or interfering with oligomerization of the protein.
Expression of nitrite reductase in Nitrosomonas europaea involves NsrR, a novel nitrite‐sensitive transcription repressor
Authors: Beaumont Hubertus J. E. , Lens Sylvia I. , Reijnders Willem N. M. , Westerhoff Hans V. , Van Spanning Rob J. M.
Published: September 2004

Production of nitric oxide (NO) and nitrous oxide (N2O) by ammonia (NH3)‐oxidizing bacteria in natural and man‐made habitats is thought to contribute to the undesirable emission of NO and N2O into the earth's atmosphere. The NH3‐oxidizing bacterium Nitrosomonas europaea expresses nitrite reductase (NirK), an enzyme that has so far been studied predominantly in heterotrophic denitrifying bacteria where it is involved in the production of these nitrogenous gases. The finding of nirK homologues in other NH3‐oxidizing bacteria suggests that NirK is widespread among this group; however, its role in these nitrifying bacteria remains unresolved. We identified a gene, nsrR, which encodes a novel nitrite (NO2–)‐sensitive transcription repressor that plays a pivotal role in the regulation of NirK expression in N. europaea. NsrR is a member of the Rrf2 family of putative transcription regulators. NirK was expressed aerobically in response to increasing concentrations of NO2– and decreasing pH. Disruption of nsrR resulted in the constitutive expression of NirK. NsrR repressed transcription from the nirK gene cluster promoter (Pnir), the activity of which correlated with NirK expression. Reconstruction of the NsrR‐Pnir system in Escherichia coli revealed that repression by NsrR was reversed by NO2– in a pH‐dependent manner. The findings are consistent with the hypothesis that N. europaea expresses NirK as a defence against the toxic NO2– that is produced during nitrification.
Versatility of the carboxy‐terminal domain of the α subunit of RNA polymerase in transcriptional activation: use of the DNA contact site as a protein contact site for MarA
Authors: Dangi Bindi , Gronenborn Angela M. , Rosner Judah L. , Martin Robert G.
Published: September 2004

The transcriptional activator, MarA, interacts with RNA polymerase (RNAP) to activate promoters of the mar regulon. Here, we identify the interacting surfaces of MarA and of the carboxy‐terminal domain of the α subunit of RNAP (α‐CTD) by NMR‐based chemical shift mapping. Spectral changes were monitored for a MarA‐DNA complex upon titration with α‐CTD, and for α‐CTD upon titration with MarA‐DNA. The mapping results were confirmed by mutational studies and retention chromatography. A model of the ternary complex shows that α‐CTD uses a ‘265‐like determinant’ to contact MarA at a surface distant from the DNA. This is unlike the interaction of α‐CTD with the CRP or Fis activators where the ‘265 determinant’ contacts DNA while another surface of the same α‐CTD molecule contacts the activator. These results reveal a new versatility for α‐CTD in transcriptional activation.
Cell cycle‐dependent abundance, stability and localization of FtsA and FtsQ in Caulobacter crescentus
Authors: Martin Miriam E. , Trimble Michael J. , Brun Yves V.
Published: September 2004

Coordination between cell division and DNA replication is ensured by checkpoints that act through proteins required for cell division. Following a block in DNA replication, transcription of the cell division progression genes ftsA and ftsQ is prevented in Caulobacter crescentus. One requirement for this checkpoint is that FtsA and/or FtsQ should be limiting for division in the next cell cycle. We show that the number of FtsA and FtsQ molecules fluctuates such that their concentration is low in swarmer and stalked cells, peaks in pre‐divisional cells, and then dramatically decreases after cell division. Despite constitutive expression from an inducible promoter, FtsA and FtsQ levels still vary during the cell cycle, and the half‐life of FtsA increases from 13 min in swarmer cells to 55 min in stalked cell types, confirming cell type‐specific degradation. The post‐division degradation of FtsA and FtsQ in swarmer cells reduces their concentration to 7% and 10% of their maximal level, respectively, strongly suggesting that de novo synthesis of both proteins is required for each division cycle. The localization of FtsA and FtsQ is also cell type‐specific. FtsA and FtsQ are recruited to the midcell during a short period in late pre‐divisional cells, consistent with the demonstrated requirement of FtsA for late stages of cell division. As previously reported for FtsZ, constitutive expression of FtsA causes cell division defects. These results indicate that the tight control of FtsA, and probably FtsQ, by cell cycle transcription, proteolysis, and localization are critical for optimal cell division and the coordination of cell division with the DNA replication cycle.
Phase variable desialylation of host proteins that bind to Streptococcus pneumoniae in vivo and protect the airway
Authors: King Samantha J. , Hippe Karen R. , Gould Jane M. , Bae Deborah , Peterson Scott , Cline Robin T. , Fasching Claudine , Janoff Edward N. , Weiser Jeffrey N.
Published: September 2004

Most clinical isolates of Streptococcus pneumoniae consist of heterogeneous populations of at least two colony phenotypes, opaque and transparent, selected for in the bloodstream and nasopharynx, respectively. Microarray analysis revealed 24 orfs that demonstrated differences in expression greater than twofold between variants of independent strains. Twenty‐one of these showed increased expression in the transparent variants, including 11 predicted to be involved in sugar metabolism. A single genomic region contains seven of these loci including the gene that encodes the neuraminidase, NanA. In contrast to previous studies, there was no contribution of NanA to adherence of S. pneumoniae to epithelial cells or colonization in an animal model. However, we observed NanA‐dependent desialylation of human airway components that bind to the organism and may mediate bacterial clearance. Targets of desialylation included human lactoferrin, secretory component, and IgA2 that were shown to be present on the surface of the pneumococcus in vivo during pneumococcal pneumonia. The efficiency of desialylation was increased in the transparent variants and enhanced for host proteins binding to the surface of S. pneumoniae. Because deglycosylation affects the function of many host proteins, NanA may contribute to a protease‐independent mechanism to modify bound targets and facilitate enhanced survival of the bacterium.
HmsP, a putative phosphodiesterase, and HmsT, a putative diguanylate cyclase, control Hms‐dependent biofilm formation in Yersinia pestis
Authors: Kirillina Olga , Fetherston Jacqueline D. , Bobrov Alexander G. , Abney Jennifer , Perry Robert D.
Published: September 2004

The Hms+ phenotype of Yersinia pestis promotes the binding of haemin or Congo red (CR) to the cell surface at temperatures below 34°C. We previously demonstrated that temperature regulation of the Hms+ phenotype is not controlled at the level of transcription. Instead, HmsH, HmsR and HmsT are degraded upon a temperature shift from 26°C to 37°C. We used random transposon mutagenesis to identify new genes involved in the temperature‐regulated expression of the Hms phenotype. One of these genes, which we designated hmsP, encodes a putative phosphodiesterase with a conserved EAL motif. Mutations in hmsP caused formation of red colonies on CR plates at 26°C and 37°C. Strains complemented with hmsP+ on a plasmid form white colonies at both temperatures. We used a crystal violet assay and confocal laser scanning microscopy to demonstrate Hms‐dependent biofilm formation by Y. pestis cells. Y. pestis Hms+ strains grown at 26°C but not at 37°C form a biofilm on borosilicate glass surfaces. Strains that either overexpress HmsT (a GGDEF domain protein) or have a mutation in hmsP produced an extremely thick biofilm. Alanine substitutions for each of the GGEE residues (amino acids 296–299) of HmsT as well as the E506 and L508 residues of HmsP caused a loss of function. We propose that HmsT and HmsP together control the amount of biofilm produced in Y. pestis. Degradation of HmsT at 37°C may be a critical factor in controlling the temperature‐dependent expression of the Hms biofilm.