bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of the A‐line™ AEP monitor as a tool for predicting successful insertion of a laryngeal mask during sevoflurane anesthesia
Authors: Alpiger S. , Helbo‐Hansen H. S. , Vach W. , Ording H.
Published: July 2004

Background:  The use of clinical signs for assessing depth of anesthesia is unreliable during periods with little noxious stimulation. A patient may appear adequately anesthetized at one moment at a given level of stimulation, but may later, when facing other more intense stimuli, show signs of insufficient anesthesia. In order to prevent under‐ or overdosing of anesthetics, an anesthesia depth monitor that is able to predict responses to noxious stimulation would therefore be useful. Auditory evoked potentials (AEP) is one of several physiological parameters under investigation. The method has been improved by rapid extraction and conversion of the AEP curve into an index (A‐Line ARX Index™ = AAI). We aimed to determine the clinically required depth of anesthesia, measured by the A‐line™ AEP Monitor, for at least 90% probability of acceptable insertion conditions for a laryngeal mask airway (LMA).

Methods:  We studied 112 patients anesthetized by mask with increasing concentration of sevoflurane in oxygen. The monitor was programmed to give an alarm at AAI between 15 and 40 according to randomization. When the alarm sounded, the end‐expiratory sevoflurane concentration was recorded and the LMA inserted. Insertion conditions were assessed by an observer blinded to the AAI.

Results:  The ED95 and prediction probability (PK) for AAI were 14.5 (CI 7.4–21.6) and 0.76 (0.66–0.86), respectively, while the ED95 and PK for expiratory sevoflurane concentration were 4.36% (CI 3.73–4.98) and 0.95 (0.91–0.99).

Conclusions:  AAI indicates the level of depth of anesthesia necessary for acceptable laryngeal mask insertion conditions. End‐expiratory sevoflurane concentration was the better predictor.
Nitrous oxide increases the incidence of bowel distension in patients undergoing elective colon resection
Authors: AkÇa O. , Lenhardt R. , Fleischmann E. , Treschan T. , Greif R. , Fleischhackl R. , Kimberger O. , Kurz A. , Sessler D. I.
Published: July 2004

Background:  Nitrous oxide rapidly inflates gas‐filled spaces such as the intestines; but whether the resulting bowel distension is clinically important remains unclear. We therefore tested the hypothesis that nitrous oxide produces clinically important bowel distension.

Methods:  Patients scheduled for colon resection were anesthetized with isoflurane and 35% oxygen and randomly assigned to 65% nitrous oxide (n = 175) or 65% nitrogen in air (n = 169). At the end of surgery, blinded surgeons rated the degree of bowel distension as none, mild, moderate, or severe. Patients reported pain, and nausea and vomiting (PONV) 2 h after surgery. Data are reported as means (SD). P < 0.05 was statistically significant.

Results:  Morphometric and demographic data were similar in the groups. The duration of surgery was 3.0 (1.2) h in the nitrous oxide group and 3.4 (1.5) h in the air group (P = 0.017). Postoperative self‐reported pain scores (visual analog scale, 0–100 mm) were greater in the nitrous oxide group (43 [30] mm) than in the air group (35 [31] mm, P = 0.018). Although the incidence of PONV was similar in the groups, VAS scores for nausea were significantly greater in the nitrous oxide group (P = 0.040). Moderate‐to‐severe bowel distension was observed in 23% of nitrous oxide patients, but in only 9% of patients in the air group (P < 0.001). The number‐needed‐to‐harm for moderate or severe bowel distension from nitrous oxide was thus seven.

Conclusions:  Our results suggest that avoiding nitrous oxide administration during prolonged bowel operations will minimize bowel distension and possibly reduce postoperative pain related to it.
Sequential combined spinal‐epidural anesthesia for cesarean section in a woman with a double‐outlet right ventricle
Authors: Landau R. , Giraud R. , Morales M. , Kern C. , Trindade P.
Published: July 2004

The number of women with complex cyanotic heart disease reaching childbearing age is continuously increasing. For anesthesiologists, management of this ‘new’ obstetric population is particularly challenging. We report the case of a parturient with a palliated double‐outlet right ventricle, who underwent a cesarean section at 34 weeks with low‐dose sequential combined spinal‐epidural anesthesia with patient‐controlled epidural postoperative analgesia. Anesthetic considerations and specific limitations of invasive monitoring are discussed, along with a review of recent literature on maternal and neonatal complications associated with pregnancies in women with cyanotic congenital heart disease.
Intrathecal morphine provides effective and safe analgesia in children after cardiac surgery
Authors: Suominen P. K. , Ragg P. G. , Mckinley D. F. , Frawley G. , But W. W. , Eyres R. L.
Published: July 2004

Background:  The purpose of this prospective, randomized, blinded to observer study was to assess the analgesic effect and safety of intrathecal morphine (ITM) in post‐operative pain control in children after heart surgery with a sternotomy incision.

Methods:  Eighty children, 3–55 kg in body weight, undergoing elective cardiac surgery with opioid‐based anaesthesia were randomly divided into two treatment groups to receive either 20 µg/kg ITM at induction of anaesthesia or control. To standardize the protocol for administration of post‐operative rescue intravenous morphine boluses and infusion (20–60 µg/kg/h), the Cardiac Analgesic Assessment Scale (CAAS) was used.

Results:  Nine patients were excluded from the study after randomization. Thirty‐five patients were enrolled to the ITM group and 36 to the control group. The groups were similar for demographics and intra‐operative clinical characteristics. The mean time for the first intravenous morphine dose from ITM administration or equivalent time zero in the control group was significantly longer (P = 0.003) in the ITM group compared with the control group (12.3 vs. 8.7 h). Time from Paediatric Intensive Care Unit (PICU) admission to the start of intravenous morphine was also significantly longer (P = 0.01) in the ITM group (6.0 vs. 3.4 h). The total intravenous morphine consumption over the mean 19 post‐operative hours was significantly lower (P = 0.03) in the ITM group. However, the use of ITM did not result in earlier extubation or earlier discharge from the PICU. Of the 35 patients who received ITM at induction of anesthesia, 20% (n = 7) did not require any additional morphine in the PICU compared with three out of 36 control group patients. This did not reach statistical significance. The incidence of adverse events was low in both groups.

Results:  An ITM dose of 20 µg/kg had a significant (P = 0.03) intravenous morphine‐sparing effect after cardiac surgery. Effective analgesia was observed for 12 h after administration of intrathecal morphine.
Early bioavailability of paracetamol after oral or intravenous administration
Authors: Holmér Pettersson P. , Öwall A. , Jakobsson J.
Published: July 2004

Background:  Paracetamol is a peripherally acting analgesic commonly used in multimodal post‐operative pain management to reduce the need for more potent analgesics with their unwanted side‐effects. The dose and optimal galenical form for achieving analgesic concentrations is not well defined. The primary aim of this pilot project was to study the early bioavailability for two fixed doses of orally administrated paracetamol and one dose of intravenous propacetamol, all of which were given after minor surgery.

Methods:  Thirty‐five patients undergoing day surgery were divided into five groups, seven patients each. Groups received either 1 g of an ordinary paracetamol tablet, 2 g of an ordinary paracetamol tablet, 1 g of a bicarbonate paracetamol tablet, 2 g of a bicarbonate paracetamol tablet or 2 g intravenously of prodrug propacetamol. We studied the plasma concentration of paracetamol during the first 80 min after administration.

Results:  Within 40 min, intravenous propacetamol gave a median plasma paracetamol concentration of 85 µmol/l (range 65–161) and decreased thereafter. After oral administration, median plasma paracetamol concentration increased with increasing dose and time, but there were huge inter‐individual differences at all time points studied. At 80 min after oral paracetamol the median plasma concentrations were 36 and 129 µmol/l for the 1‐ and 2‐g groups, respectively, with an overall range between 0 and 306 µmol/l.

Conclusion:  Oral administration of paracetamol as part of multimodal pain management immediately post‐operatively resulted in a huge and unpredictable variation in plasma concentration compared with the intravenous administration.
Subcutaneous emphysema following severe vomiting after emerging from general anesthesia
Authors: Toprak V. , Keles G. T. , Kaygisiz Z. , Tok D.
Published: July 2004

Postoperative nausea and vomiting‐related subcutaneous emphysema is an unexpected complication, especially after uneventful surgery and anesthesia. Here we report and discuss two cases of subcutaneous emphysema following severe retching and vomiting which resolved spontaneously after several days.
Satisfying and Retaining Customers through Independent Service Representatives
Authors: Brown Steven P. , Chin Wynne W.
Published: July 2004

The degree of leverage possessed by manufacturers who outsource their customer service function to channel partners over customer satisfaction and loyalty is assessed empirically. Data provided by independent service representatives are linked with data from their customers. Results indicate that a manufacturer's support of its representatives increases their job satisfaction which, in turn, is indirectly linked to the customer satisfaction through shared perceptions of service performance and quality. However, the strength of the effects is modest, suggesting that manufacturers may need to consider direct customer contact strategies or contractual means of assuring customer satisfaction when independent service representatives “own the customer.” Conceptually, the hypothesized shared mindset model is tested against the competing affect transfer model, resulting in support for the former. Job satisfaction moderates the degree of agreement between representatives' and customers' perceptions of service performance and quality such that greater agreement occurs when job satisfaction is high.
Service Businesses and Productivity*
Authors: Schmenner Roger W.
Published: July 2004

The records of superior performance of selected service firms over many years suggest that they may be more productive than others. This article uses the Theory of Swift, Even Flow to explain why that might be true. In the process, this article improves Schmenner's 1986 service process matrix. The redefinition of the axes of this matrix and of the resulting diagonal leads to enhanced understanding of productivity for service operations and helps to explain how some leading service companies have been able to sustain their competitive positions for decades.
Ability of Experience Design Elements to Elicit Emotions and Loyalty Behaviors
Authors: Pullman Madeleine E. , Gross Michael A.
Published: July 2004

Experience design, an approach to create emotional connection with guests or customers through careful planning of tangible and intangible service elements, has gained popularity in many hospitality and retail businesses. With ever‐increasing competition, service providers seek to develop loyalty by aggressively designing, continuously innovating, and managing their customer experiences. This article explores the relationship between different service elements designed to create enhanced experience and customer loyalty. In addition, it looks at emotional responses as mediating factors between the physical and relational elements and loyalty behaviors. A model is proposed and tested with a VIP hospitality tent for an internationally renowned touring circus. Results of the study indicate that while a few design elements directly affect loyalty behavior, the relationship between most design elements and loyalty behavior is strongly mediated by eliciting certain types of emotional behavior. This connection has implications for the focus of service managers' efforts in different environments.
Net‐Based Customer Service Systems: Evolution and Revolution in Web Site Functionalities*
Authors: Piccoli Gabriele , Brohman M. Kathryn , Watson Richard T. , Parasuraman A.
Published: July 2004

Firms' Web sites are becoming an increasingly important component of their customer service systems. Yet there is a dearth of research‐based insights and guidelines concerning the roles, functionalities, and effective design of Web sites. In this article we describe and discuss findings from a three‐phase, multimethod research study aimed at filling this literature void. We first propose and validate a descriptive taxonomy of customer needs amenable to online fulfillment. Complementing this taxonomy, we next propose, and offer preliminary validation of, a five‐stage conceptual model for understanding and predicting the development of a firm's Web site design and functionality. Findings from our study suggest that firms' Web sites are by and large in the early stages of development with respect to their ultimate potential, but that executives in leading service firms have begun to conceptualize and plan for subsequent stages. We conclude the article with managerial implications and important avenues for further research.
Bottom‐up control and co‐occurrence in complex communities: honeydew and nectar determine a rainforest ant mosaic
Authors: Blüthgen Nico , E. Stork Nigel , Fiedler Konrad
Published: July 2004

Complex distribution patterns of species‐rich insect communities in tropical rainforests have been intensively studied, and yet we know very little about processes that generate these patterns. We provide evidence for the key role of homopteran honeydew and plant nectar in structuring ant communities in an Australian tropical rainforest canopy and understorey. We also test the ant visitation of these resources against predictions derived from the ‘ant‐mosaic’ hypothesis. Two ant species were highly dominant in terms of territorial behaviour and abundance:OecophyllasmaragdinaandAnonychomyrma gilberti. Both dominant ant species monopolised large aggregations of honeydew‐producing homopterans. Attended homopteran species were highly segregated between these two ant species. For the use of extrafloral and floral nectar (involving 43 ant species on 48 plant species), partitioning of ant species among plant species and between canopy and understorey was also significant, but less pronounced. In contrast to trophobioses, simultaneous co‐occurrence of different nectar foraging ant species on the same plant individuals was frequent (23% of all surveys). While both dominant ant species were mutually exclusive on honeydew and nectar sources, co‐occurrence with non‐dominant ant species on nectaries was common. The proportion of visits with co‐occurrences was low for dominant ants and high for many sub‐ordinate species. These findings support the ant mosaic theory. The differential role of honeydew (as a specialised resource for dominant ants) and nectar (as an opportunistic resource for all ants including the co‐occurring non‐dominant species) provides a plausible structuring mechanism for the Australian canopy ant community studied.
Are high Arctic terrestrial food chains really that simple? – The Bear Island food web revisited
Authors: D. Hodkinson Ian , J. Coulson Stephen
Published: July 2004

Summerhayes and Elton's (1923) “nitrogen cycle” diagram for Bear Island (Bjørnøya), Svalbard, is widely used to illustrate the organisation of high Arctic food webs. We present a revision of the terrestrial section of this food web based on 12 years work on Spitsbergen, Svalbard. The level of complexity is much greater than Summerhayes and Elton suggested and the implications for ecological theory are discussed. In particular the low level of primary productivity does not appear to restrict the length of ectotherm food chains. This may in part be due to the open nature of the ecosystem, which receives energy/nutrient subsidies in the form of allochthonous wind‐blown insects and detritus, particularly from surrounding aquatic environments. Connectivity is also significantly higher. Our data support the increasingly accepted view that many food webs presented in the literature are gross oversimplifications and that analysis of their structure can produce misleading conclusions.
Trend words in ecological core journals over the last 25 years (1978–2002)
Authors: Nobis Michael , Wohlgemuth Thomas
Published: July 2004

Ecological research has been repeatedly criticized for its general lack of progress. While it has proved difficult to reveal scientific progress, from a subjective view trends in ecology seems evident. In order to objectively detect principal trends in this broad discipline during the past 25 years (1978–2002), we performed several word and co‐word analyses on titles and abstracts of articles that appeared in five core journals of ecology: «Ecology», «Oecologia», «Oikos», «Journal of Animal Ecology» and «Journal of Ecology». A general time gradient in the use of words was evident and words with a positive trend dominated. Trend words derived from article titles were used to perform co‐word analyses on abstracts available since 1991. Besides a trend towards the study of processes most important ecological fields found are landscape ecology, biodiversity, ecosystem research, modelling, and food‐web/predator–prey interactions. A semantic map of trend words was built by ordination. In the map, words formed a continuous space with the three thematic directions «biotic», «abiotic» and «temporal & spatial» representing the classic aspects of ecological research. With respect to the obvious trends and features derived from our analyses, we suggest that the results represent real scientific progress in ecology as a pluralistic, multi‐aspect and multiple‐causation discipline. Such a progress could hardly be observed from details in sub‐disciplines.
Stylistic Fronting
Authors: Hrafnbjargarson Gunnar Hrafn
Published: July 2004

Abstract.  If stylistic fronting is analyzed as feature‐driven movement into an articulated CP‐domain, in particular FocusP in the sense of Rizzi (1997), it is possible to account for two facts about stylistic fronting that so far have received little attention, namely that stylistic fronting has semantic effects and that there are differences in stylistic fronting in subordinate clauses with no overt subject and subordinate clauses with a weak subject pronoun. In this article, I will propose that there are two types of stylistic fronting, stylistic fronting of XPs into FocusP‐Spec and stylistic fronting of heads into Focus°. Stylistic fronting of XPs can only be found in clauses with no overt subject, whereas stylistic fronting of heads can be found both in clauses with no overt subject and in clauses with a weak subject pronoun.
Putting the pieces together: identification and characterization of structural domains in the V(D)J recombination protein RAG1
Authors: De Pallabi , Rodgers Karla K.
Published: July 2004

Summary:  V(D)J recombination generates functional immunoglobulin and T‐cell receptor genes in developing lymphocytes. The recombination‐activating gene 1 (RAG1) and RAG2 proteins catalyze site‐specific DNA cleavage in this recombination process. Biochemical studies have identified catalytically active regions of each protein, referred to as the core regions. Here, we review our progress in the identification and characterization, in biophysical and biochemical terms, of topologically independent domains within both the non‐core and core regions of RAG1. Previous characterizations of a structural domain identified in the non‐core region of RAG1 from residues 265–380, referred to as the zinc‐binding dimerization domain, are discussed. This domain contains two zinc‐binding motifs, a RING finger and a C2H2 zinc finger. Core RAG1 also consists of multiple domains, each of which functions individually in one or more of the essential macromolecular interactions formed by the intact core protein. Two structural domains referred to as the central and the C‐terminal domains that include residues 528–760 and 761–979 of RAG1, respectively, have been identified. The interactions of the central and C‐terminal domains in core RAG1 with the recombination signal sequence (RSS) have contributed additional insight to a developing model for the RAG1–RSS complex.
Regulation of T‐cell receptor β‐chain gene assembly by recombination signals: the beyond 12/23 restriction
Authors: Tillman Robert E. , Wooley Andrea L. , Hughes Maureen M. , Khor Bernard , Sleckman Barry P.
Published: July 2004

Summary: Assembly of antigen receptor genes is regulated in several important contexts during lymphocyte development. This regulation occurs through modulation of gene segment accessibility to the V(D)J recombinase and/or at the level of the recombination reaction due, in part, to constraints imposed by recombination signal (RS) sequences. RSs are composed of conserved heptamer and nonamer sequences that flank relatively non‐conserved spacer sequences of either 12 or 23 base pairs. Recombination occurs only between RSs of dissimilar spacer lengths, a restriction known as the 12/23 rule. Recently, we have shown that RSs can impose significant constraints on antigen receptor gene assembly beyond enforcing the 12/23 rule. This restriction, termed B12/23, was revealed by analysis of T‐cell receptor β (TCRβ) locus rearrangements, where Dβ 12RSs and not Jβ 12RSs are capable of efficiently targeting Vβ 23RSs' rearrangement. The B12/23 restriction occurs at or prior to the DNA‐cleavage step of the V(D)J recombination reaction, relies on features of the Dβ 12RSs and Vβ 23RSs, and is not absolutely dependent on lymphoid‐specific factors other than the recombinase‐activating gene‐1 (RAG‐1) and RAG‐2 proteins. By preserving Dβ gene segment utilization, the B12/23 restriction is required, at a minimum, for the generation of a diverse repertoire of TCRβ chains.
Many levels of control of V gene rearrangement frequency
Authors: Feeney Ann J. , Goebel Peter , Espinoza Celia R.
Published: July 2004

Summary:  V, D, and J gene segments rearrange at very different frequencies. As with most biological systems, there are multiple levels of control of V gene recombination frequency, and here we review some of the work from our laboratory that addresses these various control mechanisms. One of the important factors that affect non‐random V gene rearrangement frequency is the natural heterogeneity in recombination signal sequences (RSSs). Not only does variation in the heptamer and nonamer affect rearrangement, but variation in the spacer can also dramatically affect recombination. However, there are clearly other factors which control V gene rearrangement, as revealed by the fact that genes with identical RSSs can rearrange at different frequencies in vivo. Some of these other influences most likely affect the earliest stages of control – the change from an inaccessible state to an accessible state. Transcription factors can play a role in inducing these changes. Rearrangement of many VκI genes can be induced in a non‐lymphoid cell line after ectopic expression of E2A, while neighboring VκII and VκIII genes do not rearrange, demonstrating that at least one level of control of induction of accessibility occurs at the level of the individual gene. Also, changes in chromatin structure can affect accessibility and might influence individual V gene rearrangement frequency.
Recombination‐activating gene proteins: more regulation, please
Authors: Sadofsky Moshe J.
Published: July 2004

Summary:  Developing B and T cells assemble gene segments in order to create the variable regions of immunoglobulin and T‐cell receptors required by our adaptive immune response. The chemistry of this recombination pathway requires a specific nuclease and a more general repair pathway for double‐strand breaks. A complex of the recombination‐activating gene 1 (RAG1) and RAG2 proteins provides the nuclease activity. In fact, RAG1 and RAG2 probably coordinate many steps involving the coding and signaling DNA sequences. Studies using deletion and truncation mutants of the RAG proteins demonstrate that each of these contain a functional core region, representing about two‐thirds of the polypeptides. While the core regions are sufficient to catalyze recombination in test systems, the full‐length proteins seem to show more complicated behaviors in vivo. A plausible explanation is that regions outside the core help in the proper regulation of recombination. The non‐core region of RAG1 has been found to contain a ubiquitin ligase. Regulatory functions may contribute to autoregulation of the proteins involved, fidelity of the reaction, protection of the cell from translocations, coordination of recombination with the cell cycle, and possibly modification of the chromatin structure of target DNA.
The role of the non‐homologous end‐joining pathway in lymphocyte development
Authors: Rooney Sean , Chaudhuri Jayanta , Alt Frederick W.
Published: July 2004

Summary:  One of the most toxic insults a cell can incur is a disruption of its linear DNA in the form of a double‐strand break (DSB). Left unrepaired, or repaired improperly, these lesions can result in cell death or neoplastic transformation. Despite these dangers, lymphoid cells purposely introduce DSBs into their genome to maximize the diversity and effector functions of their antigen receptor genes. While the generation of breaks requires distinct lymphoid‐specific factors, their resolution requires various ubiquitously expressed DNA‐repair proteins, known collectively as the non‐homologous end‐joining pathway. In this review, we discuss the factors that constitute this pathway as well as the evidence of their involvement in two lymphoid‐specific DNA recombination events.
The phylogenetic origins of the antigen‐binding receptors and somatic diversification mechanisms
Authors: Cannon John P. , Haire Robert N. , Rast Jonathan P. , Litman Gary W.
Published: July 2004

Summary:  The adaptive immune system arose in ancestors of the jawed vertebrates approximately 500 million years ago. Homologs of immunoglobulins (Igs), T‐cell antigen receptors (TCRs), major histocompatibility complex I (MHC I) and MHC II, and the recombination‐activating genes (RAGs) have been identified in all extant classes of jawed vertebrates; however, no definitive homolog of any of these genes has been identified in jawless vertebrates or invertebrates. RAG‐mediated recombination and associated junctional diversification of both Ig and TCR genes occurs in all jawed vertebrates. In the case of Igs, somatic variation is expanded further through class switching, gene conversion, and somatic hypermutation. Although the identity of the ‘primordial’ receptor that was interrupted by the recombination mechanism in jawed vertebrates may never be established, many different families of genes that exhibit predicted characteristics of such a receptor have been described both within and outside the jawed vertebrates. Recent data from various model systems point toward a continuum of immune receptor diversity, encompassing many different families of recognition molecules whose functions are integrated in an organism's response to pathogenic invasion. Various approaches, including both genomic and protein‐functional analyses, currently are being applied in jawless vertebrates, protochordates, and other invertebrate deuterostome systems and may yield definitive evidence regarding the presence or absence of adaptive immune homologs in species lacking adaptive immune systems. Such studies have the potential for uncovering previously unknown mechanisms of generating receptor diversity.
New concepts in the regulation of an ancient reaction: transposition by RAG1/RAG2
Authors: Chatterji Monalisa , Tsai Chia‐Lun , Schatz David G.
Published: July 2004

Summary:  The lymphoid‐specific factors, recombination‐activating gene 1 (RAG1) and RAG2, initiate V(D)J recombination by introducing DNA double‐stand breaks at specific sites in the genome. In addition to this critical endonuclease activity, the RAG proteins catalyze other chemical reactions that can affect the outcome of V(D)J recombination, one of which is transposition. While the transposition activity of the RAG proteins is thought to have been critical for the evolution of modern antigen‐receptor loci, it has also been proposed to contribute to chromosomal translocations and lymphoid malignancy. A major challenge has been to determine how the transposition activity of the RAG proteins is regulated in vivo. Although a variety of mechanisms have been suggested by recent studies, a clear resolution of this issue remains elusive.
The taming of a transposon: V(D)J recombination and the immune system
Authors: Jones Jessica M. , Gellert Martin
Published: July 2004

Summary:  The genes that encode immunoglobulins and T‐cell receptors must be assembled from the multiple variable (V), joining (J), and sometimes diversity (D) gene segments present in the germline loci. This process of V(D)J recombination is the major source of the immense diversity of the immune repertoire of jawed vertebrates. The recombinase that initiates the process, recombination‐activating genes 1 (RAG1) and RAG2, belongs to a large family that includes transposases and retroviral integrases. RAG1/2 cleaves the DNA adjacent to the gene segments to be recombined, and the segments are then joined together by DNA repair factors. A decade of biochemical research on RAG1/2 has revealed many similarities to transposition, culminating with the observation that RAG1/2 can carry out transpositional strand transfer. Here, we discuss the parallels between V(D)J recombination and transposition, focusing specifically on the assembly of the recombination nucleoprotein complex, the mechanism of cleavage, the disassembly of post‐cleavage complexes, and aberrant reactions carried out by the recombinase that do not result in successful locus rearrangement and may be deleterious to the organism. This work highlights the considerable diversity of transposition systems and their relation to V(D)J recombination.
Artemis sheds new light on V(D)J recombination
Authors: Le Deist Françoise , Poinsignon Catherine , Moshous Despina , Fischer Alain , De Villartay Jean‐Pierre
Published: July 2004

Summary:  V(D)J recombination represents one of the three mechanisms that contribute to the diversity of the immune repertoire of B lymphocytes and T lymphocytes. It also constitutes a major checkpoint during the development of the immune system. Indeed, any V(D)J recombination deficiency leads to a block of B‐cell and T‐cell maturation in humans and animal models, leading to severe combined immunodeficiency (T‐B‐SCID). Nine factors have been identified so far to participate in V(D)J recombination. The discovery of Artemis, mutated in a subset of T‐B‐SCID, provided some new information regarding one of the missing V(D)J recombinase activities: hairpin opening at coding ends prior to DNA repair of the recombination activating genes 1/2‐generated DNA double‐strand break. New conditions of immune deficiency in humans are now under investigations and should lead to the identification of additional V(D)J recombination/DNA repair factors.
In vitro and in vivo studies on the generation of the primary T‐cell receptor repertoire
Authors: Livák Ferenc
Published: July 2004

Summary:  The primary T‐cell receptor repertoire is generated by somatic rearrangement of discontinuous gene segments. The shape of the combinatorial repertoire is stereotypical and, in part, evolutionarily conserved among mammals. Rearrangement is initiated by specific interactions between the recombinase and the recombination signals (RSs) that flank the gene segments. Conserved sequence variations in the RS, which modulate its interactions with the recombinase, appear to be a major factor in shaping the primary repertoire. In vitro, biochemical studies have revealed distinct steps in these complex recombinase–RS interactions that may determine the final frequency of gene segment rearrangement. These studies offer a plausible model to explain gene segment selection, but new, more physiological approaches will have to be developed to verify and refine the mechanism by which the recombinase targets the RS in its endogenous chromosomal context in vivo.
How to keep V(D)J recombination under control
Authors: Oettinger Marjorie A.
Published: July 2004

Summary:  Breaking apart chromosomes is not a matter to be taken lightly. The possible negative outcomes are obvious: loss of information, unstable chromosomes, chromosomal translocations, tumorigenesis, or cell death. Utilizing DNA rearrangement to generate the desired diversity in the antigen receptor loci is a risky business, and it must be carefully controlled. In general, the regulation is so precise that the negative consequences are minimal or not apparent. They are visible only when the process of V(D)J recombination goes awry, as for example in some chromosomal translocations associated with lymphoid tumors. Regulation is imposed not only to prevent the generation of random breaks in the DNA, but also to direct rearrangement to the appropriate locus or subregion of a locus in the appropriate cell at the appropriate time. Antigen receptor rearrangement is regulated essentially at four different levels: expression of the RAG1/2 recombinase, intrinsic biochemical properties of the recombinase and the cleavage reaction, the post‐cleavage /DNA repair stage of the process, and accessibility of the substrate to the recombinase. Within each of these broad categories, multiple mechanisms are used to achieve the desired aims. The major focus of this review is on accessibility control and the role of chromatin and nuclear architecture in achieving this regulation, although other issues are touched upon.
Regulation of immunoglobulin heavy‐chain gene rearrangements
Authors: Chowdhury Dipanjan , Sen Ranjan
Published: July 2004

Summary:  Regulated assembly of antigen receptor gene segments to produce functional genes is a hallmark of B‐ and T‐lymphocyte development. The immunoglobulin heavy‐chain (IgH) and T‐cell receptor β‐chain genes rearrange first in B and T lineages, respectively. Both loci require two recombination events to assemble functional genes; D‐to‐J recombination occurs first followed by V‐to‐DJ recombination. Despite similarities in overall rearrangement patterns, each locus has unique regulatory features. Here, we review the characteristics of IgH gene rearrangements such as developmental timing, deletion versus inversion, DH gene segment utilization, ordered recombination of VH gene segments, and feedback inhibition of rearrangement in pre‐B cells. We summarize chromatin structural features of the locus before and during recombination and, wherever possible, incorporate these into working hypotheses for understanding regulation of IgH gene recombination. The picture emerges that the IgH locus is activated in discrete, independently regulated domains. A domain encompassing DH and JH gene segments is activated first, within which recombination is initiated. VH genes are activated subsequently and, in part, by interleukin‐7. These observations lead to a model for feedback inhibition of IgH rearrangements.
Against Supermax
Authors: Lippke Richard L.
Published: July 2004

abstract  Supermax prisons subject inmates to extreme isolation and sensory deprivation for extended periods of time. Crime reduction and retributive arguments in favour of supermax confinement are elaborated. Both types of arguments are shown to falter once the logic of the two approaches to the justification of legal punishment is made clear and evidence about the effects of supermax confinement on inmates is considered. It is also argued that many criminal offenders suffer from defects in their capacities for morally responsible action, lack sufficient opportunities to remain law‐abiding, or are understandably alienated from society and the prison regime. The implications of this more realistic picture of offenders for supermax confinement are then explored briefly.
Why Equal Opportunity is not a Valuable Goal
Authors: Kershnar Stephen
Published: July 2004

abstract  In this paper, I provide an analysis of equal opportunity. I argue that equal opportunity occurs where two or more persons with equal natural abilities and willingness to work hard have chances at various jobs that are in the aggregate of equal value. I then argue that equal opportunity is neither valuable nor something that the government ought to pursue. First, it is not clear why we should value opportunities rather than outcomes. Second, the value of equal opportunity rests on the value of interest satisfaction. However, if interest satisfaction is relatively constant across different jobs and different job opportunities, then the concern for interest satisfaction will not ground the value of equal opportunity. Third, equalizing opportunities is not in itself valuable because persons are not equally valuable. Fourth, even if equal opportunity were valuable, the government could pursue it only by trespassing on individual rights.
Right to Life, Right to Die and Assisted Suicide
Authors: Chetwynd S. B.
Published: July 2004

abstract  In 2002 Diane Pretty went to the European Court of Human Rights to gain a ruling about assisted suicide. In the course of this she argued that the right to life implied a right to die. This paper will consider, from an ethical rather than a legal point of view, how the right to life might imply (or not) a right to die, and whether this includes either a right that others shall help us die, or a right against non‐interference if others are willing to help us. It does this by comparing the right to life to conceptions of property rights. This is not because I think human life is property, but because some of our ways of talking and thinking about our control over our own lives seem to be similar to our thoughts about our control over our own property. The right to life has traditionally been taken as a negative right, that is a right that others not deprive us of life. Pretty's argument, however, seems to be moving towards a positive right, not just to remain alive, but to be enabled in doing what we want to with our lives, and thus disposing of them if we so choose. The comparison with property rights suggests that the right to die only applies if our lives are ours absolutely, and may itself be modified by the suggestion that suicide harms all of us by devaluing human life in general.
Integrating Justice and Care in Animal Ethics
Authors: Lekan Todd
Published: July 2004

abstract  In this paper I argue that the standoff between justice and care approaches to animal ethics presents us with a false dilemma. We should take justice's focus on reasoning from principles, and care's use of sympathetic awareness, as two integrated deliberative capacities necessary for the consideration of arguments for extending moral concern to animals. Such an integrated approach rests on a plausible account of the psychology of moral deliberation. I develop my argument as follows. Section I summarizes the nature of the debate between justice and care approaches to animal ethics, focusing on Brian Luke's arguments against justice approaches. Section II provides pro‐justice rebuttals to Luke's objections. These rebuttals, while largely successful against Luke's objections, do not account for the intuition that sympathy does play a central epistemological role in animal ethics. Section III explains how sympathy cognitively simulates the perspective of the other, and thus can play an epistemological role in animal ethics. I argue that the abilities to simulate the perspective of the other and to reason from moral principles can complement each other. In section IV, I argue that though it may not be desirable to use both sympathy and reasoning from principles in all moral deliberation, it is a desirable aim when offering, and considering, moral arguments for what I will term the “extensionist project” of extending over moral concern to animals. I make this idea plausible by elucidating the claim that arguments for this project are best thought of as second‐order deliberations about our first‐order deliberative life.
Subjective Character of Experience in Medical Ethics: A Reply to Atkins
Authors: Nagasawa Yujin
Published: July 2004

abstract  In a recent issue of this Journal Kim Atkins argued that Thomas Nagel's argument regarding a bat's phenomenal experience is important for understanding the value placed on patient autonomy in medical ethics. In this reply to her paper, I demonstrate that Atkins's argument (a) is based on her misinterpretations of Nagel's argument, and (b) can be established without appealing to such a controversial assumption as that which she makes.
Phenotype and Natural Killer Cell Sensitivity of a Radiation‐Induced Acute T‐Cell Leukaemia (Roser Leukaemia) in PVG Rats
Authors: Nestvold J. , Stokland A. , Naper C. , Rolstad B.
Published: July 2004

A radiation‐induced T‐cell leukaemia [Roser leukaemia (RL)] in the rat was conditioned for growth in vitro by repeated in vivo–in vitro passages. This in vitro cell line, termed RL‐T, maintained its leukaemia‐inducing property when transferred to syngeneic PVG rats. It expresses several T‐cell markers and the T‐cell α/β receptor–CD3 complex. RL‐T, furthermore, expresses major histocompatibility complex (MHC) I antigens, both classical (RT1.A) and nonclassical (RT1.C), which makes it susceptible to killing by alloreactive natural killer cells in vitro.
On Immunity Against Infections and Vaccines: Credo 2004
Authors: Zinkernagel R. M.
Published: July 2004

Resistance of vertebrate hosts against infections comprises important natural or innate resistance combined with adaptive immune responses of T and B cells. Viruses, bacteria or classical parasites all probe the limit of immune responses and of immunity. They, therefore, offer an excellent opportunity to assess the biology, physiology and molecular aspects of immune responses and help in characterizing the three basic parameters of immunology – specificity, tolerance and memory. Various experiments are summarized that indicate that the rules of antiviral, antitumour, antiorgan graft and of autoimmune responses are basically the same. The practical specificity repertoire of T and B cells is probably in the order of 104−105 specificities expressed by T cells or by neutralizing antibodies. Tolerance is best defined by rules of reactivity to eliminate infections while avoiding destruction of normal cells by complete elimination of T cells that are specific for antigens persisting within the blood and lymphatic (lymphohaemopoietic) system. Induction of a T‐cell response is the result of antigens newly entering lymph nodes or spleen, initially in a local fashion and exhibiting an optimal distribution kinetics within the lymphohaemopoietic system. Antigen staying outside lymphatic tissues are immunologically ignored (e.g. are non‐events). Thus immune reactivity is regulated by antigen dose, time and relative distribution kinetics. Memory is the fact that a host is resistant against disease caused by reinfection with the same agent. Memory correlates best with antigen‐dependent maintenance of elevated antibody titres in serum and mucosal secretions, or with an antigen‐driven activation of T cells, such that they are protective immediately against peripheral reinfections in solid tissues. While antibodies transferred from mother to offspring are a prerequisite for the survival of otherwise unprotected immuno‐incompetent offsprings, activated memory T cells cannot be transmitted. Thus, attenuation of infections in newborns and babies by maternal antibodies is the physiological correlate of man‐made vaccines. T cells not only play an essential role in maintaining T‐help‐dependent memory antibody titres, but also in controlling the many infections that persist in a host at rather low levels (such as tuberculosis, measles and HIV).
Fibronectin Receptor Defects in NOD Mouse Leucocytes: Possible Consequences for Type 1 Diabetes
Authors: Geutskens S. B. , Mendes‐da‐Cruz D. A. , Dardenne M. , Savino W.
Published: July 2004

Integrins of the very late antigen (VLA) family mediate leucocyte traffic to lymphoid organs under physiological conditions and in chronic inflammatory situations such as autoimmunity. Accordingly, the current thinking is of a positive correlation between VLA expression and capability of the generation of autoimmunity. Herein we discuss recent findings on the defective expression of integrin‐type fibronectin receptors α4β1 (VLA‐4) and α5β1 (VLA‐5) in the non‐obese diabetic (NOD) mouse, a murine model of autoimmune insulin‐dependent diabetes mellitus. As compared with normal animals, NOD thymocytes (including the CD4+CD25+ regulatory T cells) exhibit a decrease in the membrane expression of α5β1, resulting in a functional impairment of fibronectin‐mediated interactions, including cell migration. Interestingly, thymocytes that are trapped within the giant perivascular spaces seen in NOD thymus are consistently α5β1 negative, suggesting that the progressive arrest of mature cells can be related to the α5β1 defect. Peripheral T cells also exhibit decreased α5β1 membrane expression and impaired fibronectin‐driven migration. Additionally, we observed a defect in α4β1 fibronectin receptor expression in NOD macrophages. Peritoneal, bone marrow‐derived‐precursor, as well as thymic macrophages of NOD mice showed an impaired upregulation of α4‐integrin chain expression, dependent on the level of macrophage maturation. Overall these data lead to the notion that NOD leucocytes bear distinct fibronectin receptor‐mediated cell migration defects, which may be involved in the pathogenesis and/or pathophysiology of the autoimmune events seen in NOD mice. Further studies will be helpful to define whether or not this concept can be applied for other autoimmune diseases.
Transcranial direct current stimulation disrupts tactile perception
Authors: Rogalewski Andreas , Breitenstein Caterina , Nitsche Michael A. , Paulus Walter , Knecht Stefan
Published: July 2004

The excitability of the cerebral cortex can be modulated by various transcranial stimulation techniques. Transcranial direct current stimulation (tDCS) offers the advantage of portable equipment and could, therefore, be used for ambulatory modulation of brain excitability. However, modulation of cortical excitability by tDCS has so far mostly been shown by indirect measures. Therefore, we examined whether tDCS has a direct behavioral/perceptional effect. We compared tactile discrimination of vibratory stimuli to the left ring finger prior to, during and after tDCS applied for 7 min at 1‐mA current intensity in 13 subjects. Stimulation was pseudorandomized into cathodal, anodal and sham conditions in a within‐subject design. The active electrode was placed over the corresponding somatosensory cortex at C4 according to the 10–20 EEG system and the reference electrode at the forehead above the contralateral orbita. Cathodal stimulation compared with sham induced a prolonged decrease of tactile discrimination, while anodal and sham stimulation did not. Thus, cortical processing can be modulated in a behaviorally/perceptually meaningful way by weak transcranial current stimulation applied through portable technology. This finding offers a new perspective for the treatment of conditions characterized by alterations of cortical excitability.