bluuebunny/crossref_metadata_2025 huggingface dataset:
Exercise training in COPD patients: the basic questions
Authors: Gosselink R , Troosters T , Decramer M
Published: January 2003

Pulmonary rehabilitation programmes aim at improving exercise capacity, activities of daily living, quality of life and perhaps survival in patients with chronic obstructive pulmonary disease (COPD). Recently, well-designed studies investigated and confirmed the efficacy of comprehensive pulmonary rehabilitation programmes, including exercise training, breathing exercises, optimal medical treatment, psychosocial support and health education. In the present overview, the contribution of exercise training in clinical practice to the demonstrated effects of pulmonary rehabilitation is discussed by means of six basic questions. These include: 1) the significance of exercise training; 2) the optimal intensity for exercise training; 3) prescribing training modalities; 4) the effects of exercise training combined with medication, nutrition or oxygen; 5) how training effects should be maintained; and 6) where the rehabilitation programme should be performed: in-patient, out-patient or homecare? First, exercise training has been proven to be an essential component of pulmonary rehabilitation. Training intensity is of key importance. High-intensity training (>70% maximal workload) is feasible even in patients with more advanced COPD. In addition, the effects on peripheral muscle function and ventilatory adaptations are superior to low-intensity training. There is, however, no consensus on the optimal training modalities. Both walking and cycling improved exercise performance. Since peripheral muscle function has been recognized as an important contributor to exercise performance, specific peripheral muscle training recently gained interest. Improved submaximal exercise performance and increased quality of life were found after muscle training. The optimal training regimen (strength or endurance) and the muscle groups to be trained, remain to be determined. Training of respiratory muscles is recommended in patients with ventilatory limitation during exercise. The additional effects of anabolic-androgenic drugs, oxygen and nutrition are not well-established in COPD patients and need further research. In order to maintain training effects, close attention of the rehabilitation team is required. The continuous training frequency necessary to maintain training effects remains to be defined. At this point in time, out-patient-based programmes show the best results and guarantee the best supervision and a multidisciplinary approach. Future research should focus on the role of homecare programmes to maintain improvements.
Regulation of depth and composition of airway surface liquid
Authors: Widdicombe JH , Bastacky SJ , Wu DX , Lee CY
Published: January 2003

The depth and composition of human airway surface liquid (ASL) may depend on secretion from airway glands, ion transport across the surface epithelium, goblet cell discharge, transepithelial gradients in hydrostatic pressure, and surface tension. Published values for the frequency of airway glands and for the secretory rates of individual glands suggest that total gland secretion in human trachea can amount to approximately 60 microL x cm(-2) x h(-1). Volume absorption directly measured across cultures of surface epithelium from human trachea is approximately 5 microL x cm(-2) x h(-1). These flows should alter the depth of ASL at +10 and -1 microm x min(-1). We have looked for changes in ASL depth of this magnitude using low-temperature scanning electron microscopy (LT-SEM) of rapidly frozen specimens of bovine trachea. Stimulation of gland secretion with methacholine led to an initial increase in depth of approximately 25 microm x min(-1) followed by a decline at approximately 1.5 microm x min(-1). Whereas the initial increase in depth was probably due to transient gland secretion, the later decline reflected active absorption of liquid across the surface epithelium. Finally, we present preliminary data showing that LT-SEM can be combined with X-ray microanalysis to determine the elemental composition of ASL.
Pleural effusion during bromocriptine exposure in two patients with pre-existing asbestos pleural plaques: a relationship?
Authors: Knoop C , Mairesse M , Lenclud C , Gevenois PA , De Vuyst P
Published: January 2003

Two patients with pleural plaques developed pleural effusion and subsequent diffuse pleural fibrosis 50 and 39 yrs after their first exposure to asbestos. The diagnosis of benign asbestos pleural effusion was suggested, but the work-up finally suggested bromocriptine-induced pleural disease in both patients. These two cases illustrate that drug-induced pleural effusion is an important differential diagnosis of benign asbestos pleural effusion. It is, moreover, possible that pre-existing asbestos pleural lesions, or even asbestos exposure, increases the risk of developing bromocriptine-induced pleural disease.
A case of superior vena cava syndrome caused by Klebsiella pneumoniae
Authors: Kim JY , Lim CM , Koh Y , Choe KH , Kim WS , Kim WD
Published: January 2003

A 27 yr old man presented with productive cough, fever and manifestations of superior vena cava syndrome. He was an alcoholic but had been in good health until 3 days prior to admission. The physical examination, the chest radiograph and the results of the sputum culture were compatible with Klebsiella pneumoniae pneumonia of the right upper lobe. The superior vena cava scintigram using technetium-99m showed near total occlusion of the superior vena cava, while sputum cytology, chest computed tomography, and bronchoscopy were all negative for malignant aetiology. Antibiotic therapy brought about slow resolution of the pneumonia and also of the superior vena caval obstruction. The follow-up scintigram showed normalized venous flow of the superior vena cava. To our knowledge, this is the first case of superior vena cava syndrome developed in probable association with Klebsiella pneumoniae pneumonia.
Pancoast's syndrome due to chronic pneumonia by Pasteurella multocida
Authors: Ribas J , Lores L , Ruiz J , Ausina V , Morera J
Published: January 2003

Infectious causes of Pancoast's syndrome are extremely rare. We describe the case of a patient with Pancoast's syndrome due to chronic pneumonia resulting from Pasteurella multocida. The patient was not immunosuppressed and had had no contact with animals. The diagnosis was made by transthoracic needle aspiration and institution of therapy with cefuroxime-axetil resulted in resolution of his symptoms.
Pulmonary fibrosis with predominant CD8 lymphocytic alveolitis and anti-Jo-1 antibodies
Authors: Sauty A , Rochat T , Schoch OD , Hamacher J , Kurt AM , Dayer JM , Nicod LP
Published: January 2003

Interstitial lung disease (ILD) is a complication of polymyositis (PM) and dermatomyositis (DM). It often manifests itself in association with myositis-specific antisynthetase autoantibodies, among which anti-Jo-1 antibodies are the most commonly encountered. In contrast, ILD associated with anti-Jo-1 antibodies without muscle involvement is rare and not well characterized. We report four patients presenting with ILD associated with anti-Jo-1 antibodies. Histological findings of transbronchial biopsies disclosed a pattern consistent with nonspecific interstitial pneumonitis, a CD8+ lymphocytosis was found in bronchoalveolar lavage. Only one of these patients developed an "antisynthetase syndrome" with PM, after nearly 2 yrs of severe ILD. The clinical conditions of all four cases showed stabilization or improvement when cyclosporine was added to their immunosuppressive treatment. These cases confirm that a CD8+ lymphocytic interstitial lung disease may be the first, and sole manifestation of autoimmune disease associated with anti-Jo-1 antibodies. Furthermore, they suggest that this form of interstitial lung disease apparently has a poor response to steroids and cytotoxic drugs, but may respond to moderate doses of cyclosporine and azathioprine in addition to low doses of steroids.
Usefulness of procalcitonin for diagnosis of sepsis in the intensive care unit
Authors: Balci Canan , Sungurtekin Hülya , Gürses Ercan , Sungurtekin Uğur , Kaptanoğlu Bünyamin
Published: January 2003

Introduction

The diagnosis of sepsis in critically ill patients is challenging because traditional markers of infection are often misleading. The present study was conducted to determine the procalcitonin level at early diagnosis (and differentiation) in patients with systemic inflammatory response syndrome (SIRS) and sepsis, in comparison with C-reactive protein, IL-2, IL-6, IL-8 and tumour necrosis factor-α.

Method

Thirty-three intensive care unit patients were diagnosed with SIRS, sepsis or septic shock, in accordance with the American College of Chest Physicians/Society of Critical Care Medicine consensus criteria. Blood samples were taken at the first and second day of hospitalization, and on the day of discharge or on the day of death. For multiple group comparisons one-way analysis of variance was applied, with post hoc comparison. Sensitivity, specificity and predictive values of PCT and each cytokine studied were calculated.

Results

PCT, IL-2 and IL-8 levels increased in parallel with the severity of the clinical condition of the patient. PCT exhibited a greatest sensitivity (85%) and specificity (91%) in differentiating patients with SIRS from those with sepsis. With respect to positive and negative predictive values, PCT markedly exceeded other variables.

Discussion

In the present study PCT was found to be a more accurate diagnostic parameter for differentiating SIRS and sepsis, and therefore daily determinations of PCT may be helpful in the follow up of critically ill patients.
Lung recruitment manoeuvres are effective in regaining lung volume and oxygenation after open endotracheal suctioning in acute respiratory distress syndrome
Authors: Dyhr Thomas , Bonde Jan , Larsson Anders
Published: January 2003

Introduction

Lung collapse is a contributory factor in the hypoxaemia that is observed after open endotracheal suctioning (ETS) in patients with acute lung injury and acute respiratory distress syndrome. Lung recruitment (LR) manoeuvres may be effective in rapidly regaining lung volume and improving oxygenation after ETS.

Materials and method

A prospective, randomized, controlled study was conducted in a 15-bed general intensive care unit at a university hospital. Eight consecutive mechanically ventilated patients with acute lung injury or acute respiratory distress syndrome were included. One of two suctioning procedures was performed in each patient. In the first procedure, ETS was performed followed by LR manoeuvre and reconnection to the ventilator with positive end-expiratory pressure set at 1 cmH2O above the lower inflexion point, and after 60 min another ETS (but without LR manoeuvre) was performed followed by reconnection to the ventilator with similar positive end-expiratory pressure; the second procedure was the same as the first but conducted in reverse order. Before (baseline) and over 25 min following each ETS procedure, partial arterial oxygen tension (PaO2) and end-expiratory lung volume were measured.

Results

After ETS, PaO2 decreased by 4.3(0.9–9.7)kPa (median and range; P < 0.005). After LR manoeuvre, PaO2 recovered to baseline. Without LR manoeuvre, PaO2 was reduced (P = 0.05) until 7 min after ETS. With LR manoeuvre end-expiratory lung volume was unchanged after ETS, whereas without LR manoeuvre end-expiratory lung volume was still reduced (approximately 10%) at 5 and 15 min after ETS (P = 0.01).

Discussion

A LR manoeuvre immediately following ETS was, as an adjunct to positive end-expiratory pressure, effective in rapidly counteracting the deterioration in PaO2 and lung volume caused by open ETS in ventilator-treated patients with acute lung injury or acute respiratory distress syndrome.
Cost of intensive care in a Norwegian University hospital 1997–1999
Authors: Flaatten Hans , Kvåle Reidar
Published: January 2003

Aim

The present study was performed in order to document costs of intensive care in a Norwegian university hospital and to perform an average cost-effectiveness study using the expected remaining life-years in survivors after 18 months.

Materials and methods

Patients admitted to the general intensive care unit (ICU) at Haukeland University Hospital from 1997 to 1999 were followed up to 18 months post ICU using data from the Norwegian Peoples' registry. Our ICU patients have a further mortality equal to the average population in Norway from that time. By creating an age-matched and sex-matched sample of the general Norwegian population equal to survivors 18 months after ICU treatment, we could find the expected further survival time for each ICU survivor. Direct and indirect ICU expenses in the study period were retrieved using a 'top-down' method. Outcome assessment was performed using the total ICU expenses in the period divided by the sum of the life expectancy (years) in survivors after 18 months.

Results

The total ICU costs (converted to 2001 values) were € 16,697,415, excluding the costs of radiology and the use of operating theatres, which were both impossible to retrieve. A total of 1051 patients were treated, of whom 60.9% survived up to 18 months. Further total life expectancies were 24,428 years. The average costs of an ICU day and stay per patient were € 2601 and € 14,223, respectively, and the average cost per year of survival per patient was € 684.

Discussion

The absolute costs were found to be higher than recent European ICU studies reporting on the cost of ICU treatment. However, the price of a further life-year in survivors was lower and was comparable with other medical treatment.
Clinical laboratory assays for measuring anti-dsDNA antibodies. Where are we now?
Authors: Isenberg D , Smeenk R
Published: January 2003

It is over 40 years since anti-dsDNA antibodies were first described in patients with lupus. A wide variety of methods for detecting these immunoglobulins have been established. In this review, we consider the utility and practical problems that the main assays present. The clinical correlations between anti-dsDNA antibodies and clinical activity in patients with lupus is discussed.
Systematic analysis of sequences of anti-DNA antibodies—relevance to theories of origin and pathogenicity
Authors: Rahman A , Giles I , Haley J , Isenberg D
Published: January 2003

Sequence analysis of anti-DNA antibodies is important in determining the molecular features which distinguish potentially pathogenic antibodies from those which are less likely to be pathogenic. Previous analysis of murine anti-DNA antibody sequences suggested that particular murine immunoglobulin genes are used preferentiallyto encode such antibodies and that somatic mutations to arginine, asparagine and lysine may be important in the creation of DNA binding sites.

In this paper, a systematic analysis of published human anti-DNA sequences shows no strong evidence for preferential usage of particular human VH or VL genes in anti-DNA antibodies. Somatic mutations in IgG and IgA antibodies are clustered in the complementarity determining regions (CDRs) due to the effect of antigen drive. This pocess contributes to an excess of arginine, asparagine and lysine residues in these CDRs, some of which are likely to play an important role in binding to DNA. Computer modeling and in-vitro expression experiments are likely to help define the roles played by these residues in antigen binding and pathogenicity more clearly.
Molecular expression systems for anti-DNA antibodies—1
Authors: Rahman A , Haley J , Latchman D S
Published: January 2003

Molecular expression systems can be used to produce whole antibodies or antibody fragments. The properties of these expression products can be tested in assays of binding or pathogenicity. Expression systems can be used to produce large quantities of antibodies which are already well-characterized,to produce new antibodies by repertoire cloning, or to produce slight modifications in the sequences of antibodies by mutagenesis prior to expression. This paper reviews the ways in which these methods have been used to study the structure and function of human and murine anti-DNA antibodies. A consistent finding, from experiments using a range of different expression methods and antibodies, is that sequence motifs including arginine residues play a major role in binding to DNA. These motifs can be present on either the heavy or the light chain, but are particularly reported in VHCDR3.
Molecular expression systems for anti-DNA antibodies—2
Authors: Kumar S , Kalsi J K , Ravirajan C T , Latchman D S , Pearl L H , Isenberg D A
Published: January 2003

Antibodies to double-stranded DNA are the best-known serological markers of systemic lupus erythematosus, and are closely associated with its renal pathogenesis. How these antibodies recognize DNA is not fully understood.An understandingof the relationship between the functional attributes of an antibody with the three-dimensional structure of its antigen-combining site would allow an insight into the rules that dictate auto-antibody–nucleic acid interaction and consequent pathogenicity of the autoantibody. Data from such studies could assist the development of novel drugs as an approach to specific therapies that can inhibit or disrupt protein–nucleic acid interactions. A full understanding of the binding specificities can be achieved only by experimental determination of detailed three-dimensional structure of these antibodies alone, and of their complexes with specific DNA antigens. A prerequisite of such a study is the ability to produce multimilligram quantities of the antibody protein. However, these antibodies are particularly difficult to express, probably due to their DNA-binding activity. This review attempts to focus on the recent developmentson the over-expressionof anti-DNA antibody fragments in heterologous cell expression systems and their purification to homogeneity that would in turn allow their structural studies via crystallization.
Transgenic models of tolerance and autoimmunity: with special reference to systemic lupus erythematosus
Authors: Ravirajan C T , Isenberg D A
Published: January 2003

Transgenic and knockout mouse carrying rearranged antigen-receptor genes have been invaluable for the elucidation of basic mechanisms in autoimmunity and have contributed new models of human autoimmune diseases. Several examples of transgenic models expressing rearranged immunoglobulin genes have been described. These models have provided a window into the events involved in this process, allowing the development and fate of self-reactive lymphocytes to be followed in vivo. In the B cell lineage, as in T cells, self-reactive cells have been found to undergo several distinct fates in vivo: they can be physically eliminated, functionally inactivated, or they can persist unchanged or become activated. Nevertheless the precise understanding of the molecular events leading to lymphocyte deletion, anergy or activation remains a challenge.
Tumour necrosis factor alpha in systemic lupus erythematosus and anti-DNA autoantibody production
Authors: Mageed R A , Isenberg D A
Published: January 2003

Tumour necrosis factor (TNFα) is a cytokine with a wide range of diverse and at times paradoxical effects. Theseinclude immunoregulatory,lymphoid organogenesisand pro-inflammatory effects. In recent years, TNFα has become a focus of interest more for its inflammatory effects in a number of chronic autoimmune diseases. This interest culminated in the successful treatment of patients with rheumatoid arthritis, Crohn's diseases and ankylosing spondylitis with blocking antibodies or soluble TNFα receptors. Paradoxically, however, TNFα also has immunomodulatory effects in some autoimmune conditions such as lupus in some mouse models of the disease and in diabetes in the none-obese diabetic mouse. The role TNFα plays in human systemic lupus erythematosus is, however, controversial. In this article we review some of the studies carried out to elucidate the effects of TNFα in lupus disease and likely mechanisms of action. Further, we discussrecent data on the likely effects of blocking TNFα on anti-DNA autoantibody production.
Triggers for anti-chromatin autoantibody production in SLE
Authors: Dieker J WC , van der Vlag J , Berden J HM
Published: January 2003

The formation of autoantibodies against chromatin is the main feature of systemic lupus erythematosis (SLE), an autoimmune disease, which is T-cell dependent and autoantigen-driven. Historically, antibodies against dsDNA, one ofthe components of chromatin, are considered as a hallmark of SLE. However, dsDNA is poorly immunogenic. Nucleosome-specific T helper cells have been identified. These T cells propagate not only nucleosome-specific antibodies, but also anti-dsDNA antibodies Nucleosomes are formed during apoptosis by cleavage of chromatin, and evidence of disturbed apoptosis has been foundespecially in certain murine models of lupus. In addition to an increased rate of apoptosis, autoimmunity against chromatin might also result from an impaired phagocytosis ofapoptotic material, for which strong evidence has been provided by studies in certain knock-out mice (C1q, SAP, Dnase I). The induction of an immune response to nucleosomes could be enhanced by modifi cations of histones or DNA during apoptosis, altered presentation by antigen presenting cells or a viral infection. The release of nucleosomes and the formation of anti-chromatin autoantibodies result in formation of complexes, which bind to the glomerular basement membrane via heparan sulfate. This deposition incites glomerulonephritis, the most serious manifestation of SLE.
Antigenic triggers and molecular targets for anti-double-stranded DNA antibodies
Authors: Deocharan B , Qing X , Beger E , Putterman C
Published: January 2003

While anti-double-stranded (ds)DNA antibodies are a characteristic serologic hallmark for SLE, the triggering antigen is unknown. Using phage display libraries, we identified DWEYSVWLSN as a peptide mimic of DNA for a pathogenic anti-dsDNA antibody. Peptide immunization of non-autoimmune mice induced anti-dsDNA as well as other lupus-associated antibodies. Molecular analysis of the induced anti-dsDNA antibodies revealed several similarities with anti-dsDNA antibodies that appear spontaneously in lupus mice. Furthermore, lupus-prone mice immunized with this peptide DNA mimic had higher auto antibody titers as well as more severe nephritis. Anti-DNA antibodies may contribute to lupus nephritis via cross-reactivity with renal antigen. Using western blotting of lysates of mesangial cells from a lupus mouse, we found that a pathogenic anti-DNA antibody binds to α-actinin. High titers of anti-α-actinin antibodies were present in the sera and kidney eluates of lupus mice with active disease. Binding to α-actinin was diminished in mesangial cells derived from BALB/c mice, suggesting that target antigen expression may play a role in determining autoantibody binding to the kidney. We conclude that a pathogenic, lupus-like autoantibody response can be induced by a peptide antigen, and that α-actinin is a cross-reactive renal target for the pathogenic anti-dsDNA autoantibody response in lupus mice.
Disturbances in peripheral blood B cell subpopulations in autoimmune patients
Authors: Potter K N , Mockridge C I , Rahman A , Buchan S , Hamblin T , Davidson B , Isenberg D A , Stevenson F K
Published: January 2003

A variety of cell surface markers are being used to identify B cell subpopulations in peripheral blood. Currently at least eight subpopulationshave been identified. Analyses of healthy individuals indicate that in general the various B cell subpopulations exist in relatively similar ratios in unrelated individuals. It has been demonstrated that B lymphocyte homeostasis is disturbed during infection and autoimmune disease. In this review we compare the distribution of B cell subpopulations in the peripheral blood of patients with systemic lupus erythematosus, rheumatoid arthritis and primary Sjogren's syndrome with each other, and with healthy individuals. The different autoimmune diseases have distinct changes in the B cell subpopulations. Understanding the nature of these B subpopulation signatures will potentially impact understanding the mechanisms of disease, diagnosis and therapy.
The role of VH determinants in systemic lupus erythematosus
Authors: Kalsi J K , Hahn B H
Published: January 2003

The V-regions of anti-DNA antibodies contain determinants which can drive the autoimmune in SLE. Most of the evidence comes from murine studies where VH-derived epitopes accelerate the disease process in lupus prone-mice and can elicit mild inflammatory changes reminiscent of lupus in healthy animals. T helper cells reactive with VH peptides arise spontaneously during the disease and are thought to assist production of both anti-peptide antibodies and the generation of autoantibodies that deposit in the glomeruli. In mice stimulatory epitopes may be unique to autoantibodies. As tolerogens VH peptides may delay or diminish the autoimmune response by altering the production of cytokines. An artificial VH peptide, (pCONCENSUS) has been derived and this inhibits responses to VH and other autoantigens but leaves the murine immune system intact and able to generate reponses to external antigens. Limited number of studies of V-region determinants of human anti-DNA MAbs indicate prior sensitization of lupus T cells to VH determinants and that V-region reactive T cells are not deleted in periphery of healthy individuals.
Lowering anti-dsDNA antibodies—what's new?
Authors: Schiffer L E , Hussain N , Wang X , Huang W , Sinha J , Ramanujam M , Davidson A
Published: January 2003

Antibodies to dsDNA are specific to SLE and are pathogenic, both due to their ability to deposit in tissues through a variety of mechanisms, and to their ability, when present in immune complexes, to activate inflammatory cells. The relationship of serum anti-dsDNA antibody levels to disease activity is a complex one and the factors that determine whether or not such antibodies will be pathogenic in an individual SLE patient are incompletely understood. Although anti-dsDNA antibodies can be made by naüve B cells and B cells belonging to the B1 and marginal zone subsets, pathogenic anti-dsDNA antibodies have the hallmarks of germinal center development and exposure to T cell help, including accumulation of somatic mutations and class switching to the IgG isotype. Epitope spreading may result in aquisition of cross-reactivities with multiple target organ antigens and aquisition of a memory phenotype will allow these B cells to acquire antigen presentation functions that amplify the autoreactive response. In the early stages of disease, or after remission induction protocols, autoreactive B cells may be susceptible to treatments that target T cell costimulation or that deplete or tolerize naüve and mature B cells. Therapeutic approaches targeting innate immune responses or regulatory T cells are starting to be tested in pre-clinical models. In later disease stages, memory and plasma cell accumulation may render patients more resistant to this type of therapeutic approach. Deposition of anti-dsDNA antibodies in target tissues can stimulate an inflammatory cascade that leads to tissue damage. A number of murine models have now been developed that show that interruption of this cascade can prevent or reverse such damage. This type of approach may be beneficial for individuals with established disease. As we learn more about the specific defects that cause SLE, it may become possible to individualize therapy based on patient specific biologic markers.
Anti-DNA antibodies - overview of assays and clinical correlations
Authors: Rahman A , Hiepe F
Published: January 2003

Many authors have studied the links between levels of anti-dsDNA antibodies and disease activity in patients with SLE. Interpretationof these studies must take into account the facts that there are a range of possible assays for anti-dsDNA and a number of indices available for assessing disease activity. A recent study compared levels of various autoantibodies with organ specific disease activity assessed during the British Isles Lupus Assessment Group (BILAG) index. Amti-dsDNA and anti-heparan sulphate levels were more likely to be raised in patients with renal than non-renal disease.

Some anti-DNA antibodies are actually anti-nucleosome antibodies, which lose DNA reactivity when purified under dissociating conditions. Patients with SLE have significantly increased levels of nucleosomes in their sera compared with healthy controls. In patients with SLE, reduced clearance of nucleosomes released from apoptotic cells may induce the formation of antinucleosome antibodies.
Structural considerations of autoantibodies
Authors: Madaio M P , Naparstek Y
Published: January 2003

The mechanisms responsible for peptide-induced immunosuppression lupus-prone BWF1 mice were determined to be mediated via recognition by T cells, although the response was peptidespecific, as some accelerated the autoimmune response. Furthermore, this was associated with suppressionof IFN-g and IL-4 in serum and increased TGF-b. Recent isolation of peptide-specific T cells should be helpful in sorting out the mechanisms responsible for these events. In separate studies, it was demonstrated that an anti-DNA antibody that enters cells is able to transport proteins linked to it, supporting the possibility that this system can be used as a therapeutic modality to modify specific cellular activities.
Anti-DNA antibodies—structure and function
Authors: Rahman A , Kumar S , Potter K N
Published: January 2003

Expression of monoclonal anti-DNA antibodies in vitro can be used to study the relationships between molecular structure, binding properties and pathogenicity.Bacterial and yeast systems can be used to produce antibody fragments such as Fab. The yields are potentially sufficient to allow structural studies such as crystallization, but purification of the anti-DNA Fab from the bacterial periplasm may be challenging. Mammalian cell expression systems produce lower yields, but the products are whole antibodies, which can be used in assays of pathogenicity. This article describes some recent experiments in which bacterial and mammalian systems were used to study human monoclonal anti-DNA antibodies. Light chain sequence motifs were found to be important both in binding to antigens and in determining pathogenicity of the antibodies in severe combined immunodeficiency mice. The distribution of B cell subpopulations is disturbed in patients with systemic lupus erythematosus (SLE). These patients, like those with infectious mononucleosis, have an overall B cell lymphopenia but an increased frequency of plasmablasts/early plasma cells in their blood. Some of these early plasma cells belong to clones that have rearranged the VH gene V4-34. There is a selective rise in immunoglobulins encoded by this gene in both infectious mononucleosis and SLE.
Antigenic targets–workshop report
Authors: Winkler T
Published: January 2003

Several excellent animal models for systemic lupus erythematosus are available to study the pathogenetic mechanisms of anti-DNA antibodies, immunological mechanisms for their origin and the influence of susceptibility genes for the development of anti-DNA antibodies. Furthermore several transgenic mice have been generated to study B cell tolerance against DNA. During the meeting recent progress on animal models for systemic lupus erythematosuswas discussed.
Cross-reactivity and pathogenicity of anti-DNA autoantibodies in systemic lupus erythematosus
Authors: Mageed R A , Zack D J
Published: January 2003

Autoantibodies to DNA were discovered over 40 years ago following the discovery a few years earlier of the ‘LE’ cell phenomenon by Hargraves and colleagues in 1948. These investigators noted that, when leucocytes were incubated with serum from lupus patients, changes in the nucleus could be seen together with phagocytosis of nuclear remnants by polymorphonuclear leucocytes. Since that time numerous studies in many laboratories have investigated almost every aspect of anti-DNA antibodies, partly to identify what determines their pathology. Whilst a subset of antiDNA antibodies, especially anti-native, or double-stranded DNA (dsDNA) antibodies constitutes a hallmark of lupus disease and a diagnostic criterion, it is now clear that not all anti-DNA autoantibodies are of pathogenic relevance. Moreover, anti-DNA autoantibodies may also be found in other connective tissue disorders. Here we briefly review studies presented at the fifth international workshop on anti-DNA autoantibodiesheld in London to highlight relevant properties of pathogenic anti-DNA antibodies.
Apoptosis and nucleosomes
Authors: Stollar B D , Stephenson F
Published: January 2003

Drs Berden and Koutouzov presented evidence that nucleosomes are antigens in lupus pathogenesis and that apoptotic cells are the source of nucleosomes. Berden's group measured persistence of circulating nucleosomes and nucleosome–antibody complexes in autoimmune mice and demonstrated nucleosomaldepositionin skin of SLE patientsas well as in renal lesions. Koutouzovreported that anti-nucleosomes are among the earliest autoantibodies in MRL‡/‡ mice, appearing several weeks before anti-DNA antibodies. Treatment of the mice with a pro-apoptotic drug, taxote ‘re, accelerated autoantibodyproductionand developmentof lesions. Herrmann proposed that persistent immunization results from reduced dead cell clearance and reduced production of immunosuppressive cytokines by defective scavenger macrophages. He also described accumulation of apoptotic cells in germinal follicles in SLE patients and attachment of nuclear antigens that are produced in apoptosis to the surface of follicular dendritic cells. Apoptosis-derived nucleosomes may be important in both the immunizing and effector arms of pathogenesis.
T cell—B cell interactions
Authors: Ehrenstein M R , Hahn B
Published: January 2003

This session had as its central theme the analysis of peptide epitopes and their relationship with lupus pathogenesis. New information on the role of peptides opens up the possibility of treatments based on inducing immunological tolerance although care needs to be taken since it is diffi cult to predict flare or remission of disease after exposure to critical antigenic peptides. The provenance of these peptides may be self or foreign antigens, or autoantibody idiotypes.
Workshop report on some new ideas about the treatment of systemic lupus erythematosus
Authors: Linnik M , Staines N A , Berden J , Isenberg D A
Published: January 2003

Our increased understandingof the pathogenesisof systemic lupus erythematosus is leading to new ideas about its therapy. In this session of the workshop the use of LJP 394 a B cell toleragen and the use of an anti-CD20 monoclonal antibody were discussed in some detail. Their rationale and early clinical results were reviewed; both have shown encouraging clinical and serological benefi t. Defi nitive double-blind clinical trials are still, however, awaited. In addition, the intriguing notion of using a nasal instillation of a histone peptide was described and early work in an experimental model presented.
Analysis of uncertainty in health care cost-effectiveness studies: an introduction to statistical issues and methods
Authors: O’Brien B J , Briggs A H
Published: January 2003

Cost-effectiveness analysis is now an integral part of health technology assessment and addresses the question of whether a new treatment or other health care program offers good value for money. In this paper we introduce the basic framework for decision making with cost-effectiveness data and then review recent developments in statistical methods for analysis of uncertainty when cost-effectiveness estimates are based on observed data from a clinical trial. Although much research has focused on methods for calculating confidence intervals for cost-effectiveness ratios using bootstrapping or Fieller’s method, these calculations can be problematic with a ratio-based statistic where numerator and=or denominator can be zero. We advocate plotting the joint density of cost and effect differences, together with cumulative density plots known as cost-effectiveness acceptability curves (CEACs) to summarize the overall value-for-money of interventions. We also outline the net-benefit formulation of the cost-effectiveness problem and show that it has particular advantages over the standard incremental cost-effectiveness ratio formulation.
Bayesian methods for design and analysis of cost-effectiveness trials in the evaluation of health care technologies
Authors: O’Hagan A , Stevens J W
Published: January 2003

We review the development of Bayesian statistical methods for the design and analysis of randomized controlled trials in the assessment of the cost-effectiveness of health care technologies. We place particular emphasis on the benefits of the Bayesian approach; the implications of skew cost data; the need to model the data appropriately to generate efficient and robust inferences instead of relying on distribution-free methods; the importance of making full use of quantitative and structural prior information to produce realistic inferences; and issues in the determination of sample size. Several new examples are presented to illustrate the methods. We conclude with a discussion of the key areas for future research.
Decision analytical economic modelling within a Bayesian framework: application to prophylactic antibiotics use for caesarean section
Authors: Cooper N J , Sutton A J , Abrams K R
Published: January 2003

Economic evaluation of health care interventions based on decision analytic modelling can generate valuable information for health policy decision makers. However, the usefulness of the results obtained depends on the quality of the data input into the model; that is, the accuracyof the estimates for the costs, effectiveness, and transition probabilities between the different health states of the model. The aim of this paper is to review the use of Bayesian decision models in economic evaluation and to demonstrate how the individual components required for decision analytical modelling (i.e., systematic review incorporating meta-analyses, estimation of transition probabilities, evaluation of the model, and sensitivity analysis) may be addressed simultaneously in one coherent Bayesian model evaluated using Markov Chain Monte Carlo simulation implemented in the specialist Bayesian statistics software WinBUGS. To illustrate the method described, a simple probabilistic decision model is developed to evaluate the cost implications of using prophylactic antibiotics in caesarean section to reduce the incidence of wound infection. The advantages of using the Bayesian statistical approach outlined compared to the conventional classical approaches to decision analysis include the ability to: (i) perform all necessary analyses, including all intermediate analyses (e.g., meta-analyses) required to derive model parameters, in a single coherent model; (ii) incorporate expert opinion either directly or regarding the relative credibility of different data sources; (iii) use the actual posterior distributions for parameters of interest (opposed to making distributional assumptions necessary for the classical formulation); and (iv) incorporate uncertainty for all model parameters.
Measuring uncertainty in complex decision analysis models
Authors: Parmigiani G
Published: January 2003

Prediction models used in support of clinical and health policy decision making often need to consider the course of a disease over an extended period of time, and draw evidence from a broad knowledge base, including epidemiologic cohort and case control studies, randomized clinical trials, expert opinions, and more. This paper is a brief introduction to these complex decision models, their relation to Bayesian decision theory, and the tools typically used to describe the uncertainties involved. Concepts are illustrated throughout via a simplified tutorial.
Using inverse-weighting in cost-effectiveness analysis with censored data
Authors: Willan A R , Lin D Y , Cook R J , Chen E B
Published: January 2003

Due to induced dependent censoring, estimating mean costs and quality-adjusted survival in a cost-effectiveness analysis using standard life-table methods leads to biased results. In this paper we propose methods for estimating the difference in mean costs and the difference in effectiveness, together with their respective variances and covariance in the presence of dependent censoring. We consider the situation in which the measure of effectiveness is either the probability of patients surviving a duration of interest, mean survival time over a duration of interest or mean quality-adjusted survival time over a duration of interest. The method of inverse-weighting is used for censored cost and quality of life data. The methods are illustrated in an example using an incremental net benefit analysis.
Promoting the Dignity of the Child in Hospital
Authors: Reed Paula , Smith Pam , Fletcher Margaret , Bradding Angela
Published: January 2003

This article aims to deconstruct the concept of dignity in a way that is meaningful, in particular to nurses and other health workers who seek to promote the dignity of children in their care. Despite the emphasis in a variety of codes and policies to promote dignity, there is a lack of a clear definition of dignity in the literature. In particular there is little reference to dignity, theoretically or empirically, as it relates to children. Without clarity it is not possible to act in an ethical way on behalf of children whose dignity could otherwise be compromised.

The theoretical position taken has evolved from the medico-nursing and philosophical discourse concerning the nature of human dignity and more recent sociological texts that discuss the social construction of the child and childhood.

The article is further influenced by additional insights derived from an ethnographic pilot study at a large district general hospital. This study was undertaken in an attempt to appreciate the subjective experience of dignity by children, and to begin to address the empirical gap in the literature and promote discussion.

The concept of a macro and a micro dignity is discussed, together with the role of the nurse in articulating the relationship between the two. The importance of control and witnesses in the experience of dignity is discussed and, finally, also the ethical implications when seeking to promote the dignity of children.
The Role of Older People in Our Communities
Authors: Shotton Leila
Published: January 2003

The proportion of older people in the total population is increasing in most countries because of advances in medical technology and resulting longer life expectancy. The role that older people play in our communities does not reflect this. Sometimes they are reduced to mere statistics and stereotypes in economic and political discussions on the financial burdens of care for older people. I argue that we need to rebuild inclusive communities in which older people are respected as valuable members. I suggest that this can be done by studying the characteristics of past communities and by learning from the work of environmental ethicists who advocate the preservation of our heritage. Nurses share with them a holistic perspective on complex issues such as ageing. They are therefore in a position to empower older people to play a role in our communities as unique individuals with integrity and wisdom.
Perceptions of Autonomy, Privacy and Informed Consent in the Care of Elderly People in Five European Countries: general overview
Authors: Leino-Kilpi Helena , Välimäki Maritta , Dassen Theo , Gasull Maria , Lemonidou Chryssoula , Schopp Anja , Scott P Anne , Arndt Marianne , Kaljonen Anne
Published: January 2003

Ethical issues in the care of elderly people have been identified in many countries. We report the findings of a comparative research project funded by the European Commission, which took place between 1998 and 2001. The project explored the issues of autonomy (part I), privacy (part II) and informed consent (part III) in nursing practice. Data were collected from elderly residents/patients (n = 573) and nursing staff (n = 887) in five European countries: Finland, Spain, Greece, Germany and the UK (Scotland). Questionnaires were used as the data collection tool (self-completion questionnaires for staff, structured interviews for the elderly participants). Four basic nursing interventions in the care of elderly people were targeted: hygiene, fluid intake and nutrition, medication, and elimination. The data were analysed statistically. The results indicated differences within all five countries between staff and patient perceptions of autonomy, privacy and informed consent. There were also similar differences between individual countries. Conclusions were reached concerning practice, education and research.

This is the first of a set of five articles published together in this issue of Nursing Ethics in which the results of this comparative research project are presented.
Perceptions of Autonomy in the Care of Elderly People in Five European Countries
Authors: Scott P Anne , Välimäki Maritta , Leino-Kilpi Helena , Dassen Theo , Gasull Maria , Lemonidou Chryssoula , Arndt Marianne , Schopp Anja , Suhonen Riitta , Kaljonen Anne
Published: January 2003

The focus of this article is perceptions of elderly patients and nurses regarding patients’ autonomy in nursing practice. Autonomy is empirically defined as having two components: information received/given as a prerequisite and decision making as the action. The results indicated differences between staff and patient perceptions of patient autonomy for both components in all five countries in which this survey was conducted. There were also differences between countries in the perceptions of patients and nurses regarding the frequency with which patients received information from nursing staff or were offered opportunities to make decisions.

This is the second of a set of five articles published together in this issue of Nursing Ethics in which the results of this comparative research project are presented.
Perceptions of Privacy in the Care of Elderly People in Five European Countries
Authors: Schopp Anja , Leino-Kilpi Helena , Välimäki Maritta , Dassen Theo , Gasull Maria , Lemonidou Chryssoula , Scott P Anne , Arndt Marianne , Kaljonen Anne
Published: January 2003

The focus of this article is on elderly patients’ and nursing staff perceptions of privacy in the care of elderly patients/residents in five European countries. Privacy includes physical, social and informational elements. The results show that perceptions of privacy were strongest in the UK (Scotland) and weakest in Greece. Country comparisons revealed statistically significant differences between the perceptions of elderly patients and also between those of nurses working in the same ward or long-term care facility. Perceptions of privacy by patients and their nursing staff were quite similar in Finland, Germany and the UK. In contrast, in Greece and Spain these perceptions were different: nurses believed that they took account of their patients’ privacy needs more often than the patients themselves felt this was the case. Among Spanish and UK patients, an association was found between lower levels of independence and comparatively less positive perceptions of privacy. No associations were established between nurses’ perceptions and their demographic factors.

This is the third of a set of five articles published together in this issue of Nursing Ethics in which the results of this comparative research project are presented.