Invited article: Electric solar wind sail: toward test missions.

The electric solar wind sail (E-sail) is a space propulsion concept that uses the natural solar wind dynamic pressure for producing spacecraft thrust. In its baseline form, the E-sail consists of a number of long, thin, conducting, and centrifugally stretched tethers, which are kept in a high positive potential by an onboard electron gun. The concept gains its efficiency from the fact that the effective sail area, i.e., the potential structure of the tethers, can be millions of times larger than the physical area of the thin tethers wires, which offsets the fact that the dynamic pressure of the solar wind is very weak. Indeed, according to the most recent published estimates, an E-sail of 1 N thrust and 100 kg mass could be built in the rather near future, providing a revolutionary level of propulsive performance (specific acceleration) for travel in the solar system. Here we give a review of the ongoing technical development work of the E-sail, covering tether construction, overall mechanical design alternatives, guidance and navigation strategies, and dynamical and orbital simulations.

Social and early-life determinants of overweight and obesity in 18-year-old Swedish men.

OBJECTIVES: To investigate the combined effects of size at birth and maternal education on prevalence of overweight and obesity among 18-year-old men. METHODS: We studied the associations of weight for gestational age and maternal education with body mass index (BMI), overweight and obesity by multivariate linear and logistic regression, adjusted for mother's age, parity and diabetes in a register-based cohort of 6535 men born between 1973 and 1985. Further adjustments for mother's height, pre-pregnancy weight, weight gain and smoking during pregnancy were made in a subsample of 1103 men born between 1982 and 1985. RESULTS: Mean BMI and prevalence of overweight and obesity decreased with higher maternal education. Mother's BMI and smoking were the strongest predictors of sons' overweight and obesity and essentially accounted for the variation in son's overweight by maternal education. The association of size at birth with later overweight was present only in sons born to mothers who were nonsmokers (odds ratio per 1 standard deviation weight for gestational age z-score 1.46, 95% CI 1.18-1.81) and became substantially reduced on adjustment for mother's pre-pregnancy BMI. Length of gestation was not statistically significantly associated with BMI at age 18. CONCLUSIONS: Maternal overweight and maternal smoking were the strongest determinants of offspring overweight and its social patterning, and should be a priority for public health policies.

Role of peptidoglycan subtypes in the pathogenesis of bacterial cell wall arthritis.

BACKGROUND: Bacterial cell wall (CW) arthritis develops in susceptible strains of rats after a single intraperitoneal injection of the CW from certain bacterial species, both pathogenic and non-pathogenic. For the development of chronic bacterial CW arthritis, the structure of the bacterial peptidoglycan (PG) has been found to be decisive. OBJECTIVE: To define the role of PG subtypes in the pathogenesis of chronic bacterial CW arthritis. METHOD: Arthritis was induced with CWs of Lactobacillus plantarum, L casei B, L casei C, and L fermentum. Gas chromatography-mass spectrometry was used to measure the presence of CW derived muramic acid in the liver and to determine PG subtypes. CWs were also tested for their resistance to lysozyme in vitro. RESULTS: These results and those published previously indicate that PGs of CWs which induce chronic arthritis, no matter whether they were derived from strains of Streptococcus, Bifidobacterium, Collinsella, or Lactobacillus, all have lysine as the third amino acid of the PG stem peptide, representing PG subtypes A3alpha and A4alpha. Those strains which induce only transient acute arthritis or no arthritis at all do not have lysine in this position, resulting in different PG subtypes. CONCLUSIONS: In vivo degradation of only those PGs with the subtypes A3alpha and A4alpha leads to the occurrence of large CW fragments, which persist in tissue and have good proinflammatory ability. CWs with other PG subtypes, even if they are lysozyme resistant, do not cause chronic arthritis, because the released fragments are not phlogistic. It is emphasised that a variety of microbial components not causing inflammation have been found in animal and human synovial tissue.

Normal intestinal microbiota in the aetiopathogenesis of rheumatoid arthritis.

A series of observations have led to the hypothesis that normal intestinal microbiota in patients with rheumatoid arthritis may harbour, for genetic reasons, bacteria with cell walls capable of inducing arthritis. Differences occur between bacterial species, and even between strains of a single species, because some cell walls induce experimental chronic arthritis, whereas some others induce only a transient acute arthritis or no arthritis at all. In susceptible subjects, with continuous seeding of bacterial products from the gut, the synovial inflammation is followed by erosion, exposition of cartilage antigens, and self perpetuating chronic arthritis.

Comparison of two budesonide powder inhalers, Easyhaler and Turbuhaler, in steroid-naïve asthmatic patients.

The objective of this multicenter study was to compare the clinical efficacy, safety, and acceptability of Easyhaler and Turbuhaler for the delivery of budesonide 200 micrograms/dose twice daily in steroid-naïve asthmatic patients. Three hundred and twenty-six newly diagnosed, steroid-naïve adult patients with mild-to-moderate asthma were recruited into this randomized, double-blind, double-dummy, parallel-group study, comprising a 2-week run-in period and 8 weeks of treatment. Patients received budesonide inhalation powder 400 micrograms/day either via Easyhaler (n = 159) or via Turbuhaler (n = 167), plus salbutamol inhalation powder (100 micrograms/dose) via Easyhaler as rescue therapy. The study was completed by 292 patients: 143 in the Easyhaler group and 149 in the Turbuhaler group. The primary outcome variable, mean morning peak expiratory flow (PEF), improved significantly and almost similarly by 36.3 and 30.6 l/min, respectively, from run-in to weeks 7-8. At weeks 7-8, the mean (SE) difference in morning PEF between the two treatments was 7.1 (9.4) l/min (90% CI from -8.4 to 22.6) on per protocol analysis, which was within the defined limits for therapeutic equivalence. There were no significant differences between treatments in terms of secondary efficacy variables or adverse events. However, patients found Easyhaler more acceptable than Turbuhaler. The results show that budesonide via Easyhaler is clinically as effective as Pulmicort Turbuhaler when equal daily doses of budesonide are delivered to steroid-naïve asthmatic patients. Moreover, patients found Easyhaler more acceptable than Turbuhaler, and a majority would prefer Easyhaler if given a choice.

Mononuclear cell response to enterobacteria and Gram-positive cell walls of normal intestinal microbiota in early rheumatoid arthritis and other inflammatory arthritides.

OBJECTIVE: To study whether enterobacteria and Gram-positive bacterial cell walls (BCW) derivedfrom normal intestinal microbiota are involved in the etiopathogenesis of early rheumatoid arthritis (RA). METHODS: Peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) were isolatedfrom patients with early RA (the average duration of 5 months) and the controls (other types of inflammatory arthritis). The mononuclear cell proliferation and tumor necrosis factor-alpha (TNF-alpha) responses to heat-killed Salmonella enteritidis (SE). Yersinia enterocolitica (YE), and Escherichia coli (EC), and to Gram-positive BCW derived from four common intestinal indigenous bacteria, Eubacterium aerofaciens (EA), Eubacterium limosum (EL), Lactobacillus casei (LC), and Lactobacillus fermentum (LF), and a BCW derived from a pathogen, Streptococcus pyogenes (SP) were investigated. RESULTS: 39% or 56% of patients with early RA showed significant proliferation responses by PBMC or SFMC against enterobacteria, respectively. In other types of arthritis, corresponding figures were 59% or 66%. When BCW were used as antigens, 8.1% or 23% of patients with early RA showed proliferation responses by PBMC or SFMC, respectively. In other types of arthritis the corresponding figures were 7.5% or 35%, respectively. However, TNF-alpha production by SFMC stimulated by EA BCW, SE, YE or EC, was significantly higher in early RA than in other types of arthritis. CONCLUSION: These results suggest that SFMC reacting with enterobacteria or BCW exist in some patients with early RA, but also in other types of inflammatory arthritis. Intestinal bacterial agents may play a role in the etiopathogenesis of RA, but the effect appears to be non-specific.

Use of a peptide based enzyme immunoassay in diagnosis of Chlamydia trachomatis triggered reactive arthritis.

OBJECTIVE: To assess the presence of circulating IgA and IgG antibodies to Chlamydia trachomatis in sera of patients with reactive arthritis (ReA) and other arthritides. METHODS: A peptide based enzyme immunoassay (EIA) was used to study 132 patients divided into 5 groups: C. trachomatis triggered ReA, uroarthritis, enteroarthritis, oligoarthritis, and rheumatoid arthritis (RA). Followup sera were available from 19 patients. RESULTS: An increased prevalence of C. trachomatis antibodies was observed in patients with ReA triggered by C. trachomatis; 18/23 (78%) had IgA and 19/23 (83%) had IgG antibodies. In patient groups with uroarthritis (n = 12), enteroarthritis (n = 56), oligoarthritis (n = 16), and RA (n = 25), C. trachomatis IgA/IgG antibodies were detected in 58%/75%, 27%/21%, 25%/31%, and 20%/32% of patients, respectively. Both the IgA and IgG antibodies were positive in 74%, 50%, 16%, 25%, and 12% of the patients with C. trachomatis triggered ReA, uroarthritis, enteroarthritis, oligoarthritis, and RA, respectively. Based on positivity of both isotypes the sensitivity of the assay was 74% and specificity 84%. In the followup sera, an association between circulating C. trachomatis-specific antibody concentrations and clinical disease outcome of the arthritis was seen in patients with culture-positive C. trachomatis triggered ReA. CONCLUSION: C. trachomatis species-specific peptide EIA correlates well with conventional diagnosis of primary C. trachomatis infection in patients with ReA. This assay may be a valuable contribution to the diagnosis of C. trachomatis triggered ReA.

Enzyme degradation and proinflammatory activity in arthritogenic and nonarthritogenic Eubacterium aerofaciens cell walls.

Two almost-identical strains of Eubacterium aerofaciens isolated from the normal human gut flora were used. The cell wall (CW) of one strain with a peptidoglycan (PG) type A4alpha induces chronic arthritis in the rat after a single intraperitoneal injection, whereas CW of the other with PG type A4beta induces only a transient acute arthritis. The CW of the arthritogenic E. aerofaciens was a twofold-more-potent stimulator of the proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and monocyte chemoattractant protein 1 (MCP-1) than the nonarthritogenic CW. After degradation with mutanolysin, the capacity of the arthritogenic PG to stimulate production of TNF-alpha and MCP-1 was significantly increased, whereas that of the nonarthritogenic PG was significantly decreased. In other words, after enzyme degradation the arthritogenic PG had a four- to fivefold-stronger stimulatory capacity than that of the enzyme-treated nonarthritogenic PG. These findings indicate that the arthritogenicity of CW or a PG is not dependent on the enzyme resistance alone but also on how the PG fragments released by enzyme degradation stimulate the production of proinflammatory cytokines.

Assessment of the systemic effects of budesonide inhaled from Easyhaler and from Turbuhaler in healthy male volunteers.

The main objective of this study was to show dose-dependent equivalence in the systemic activity of budesonide 800 microg day(-1) and 1600 microg day(-1) delivered from either Easyhaler or Turbuhaler in healthy male subjects. This single-centre study was carried out according to a randomized, double-blind, double-dummy, five-way crossover design over a 9-week period. All subjects received 1 week of treatment with the following, in randomized order, with a washout week between each treatment: budesonide Easyhaler 800 microg day(-1) plus placebo Turbuhaler; budesonide Easyhaler 1600 microg day(-1) plus placebo Turbuhaler; placebo Easyhaler plus Pulmicort Turbuhaler 800 microg day(-1); placebo Easyhaler plus Pulmicort Turbuhaler 1600 microg day(-1); placebo Easyhaler plus placebo Turbuhaler. The final inhalation of study drug was performed at the study centre, where blood and urine samples were collected. Fifteen subjects were recruited and all completed the study. Mean serum cortisol AUC0-20 values (the primary outcome variable) were comparable for each device at the two dose levels, and met the defined criteria for equivalence (90% CI 0.8-1.25 for between-treatment difference). Budesonide 800 microg day(-1) caused minimal suppression of serum cortisol AUC0-20 values, Budesonide 1600 microg day(-1) statistically significantly suppressed serum cortisol AUC0-20 values compared with placebo. Mean morning serum cortisol values were within the reference range in al treatment groups. At a budesonide dose of 800 microg day(-1) mean urine cortisol/creatinine ratio was statistically significantly higher with Easyhaler than with Turbuhaler, but there was no significant difference between the devices at the 1600 microg day(-1) dose. Serum budesonide concentrations were equivalent for each device at both dose levels. Adverse drug reactions were infrequent and mild in nature and there were no clinically significant changes in laboratory safety variables. In conclusion, in healthy male volunteers, budesonide 800 microg day(-1) and 1600 microg day inhaled from Easyhaler had comparable systemic effects to the same doses inhaled via Turbuhaler.

Reactive arthritis.

Reactive arthritis is a disease affecting mostly young adults. Owing to a greater general awareness the diagnosis has become more common during recent years. It is well established that ReA is caused by an infection, mostly in genetically susceptible individuals. The pathogenetic mechanisms are still poorly understood, and the treatment rests mainly on anti-inflammatory drugs or steroids. Vigorous and early treatment of the triggering infection may prevent the development of ReA but this is rarely possible in everyday clinical practice. Despite its name, the disease should be considered as a general disorder that affects not only the joints. The prognosis is not as good as earlier believed, and relapses or chronic development are not unusual.

Experimental chronic arthritis and granulomatous inflammation induced by bifidobacterium cell walls.

Effects of cell walls (CWs) from two almost identical strains of Bifidobacterium adolescentis were studied in rats, using three different doses. A single i.p. injection of both CWs triggered a long-lasting arthritis with CW degradation products present in the joint tissue. Histologically, the arthritis was characterized by inflammatory cells, synovial hyperplasia, pannus formation and bone erosion, closely resembling human rheumatoid arthritis (RA). In addition, CWs of the other strain induced a remarkable granuloma formation in the spleen and liver. Both CWs have the same peptidoglycan (PG) type A4alpha/beta, but differ from each other in three aspects. CW of the granuloma inducing strain: firstly has more lysine and less ornithine in PG stem peptides; secondly is more resistant to lysozyme degradation, and thirdly is better retained in the spleen. All these in comparison to the other strain used. Such characteristics are associated with the capacity to induce chronic arthritis, but it remains open how crucial they are for the granuloma formation.

From reactive arthritis to rheumatoid arthritis.

Reactive arthritis was initially described as a sterile synovitis, without microbial components present in the joint tissue. It has, however, become evident that bacterial degradation products, and even bacterial DNA, are present in the synovium of patients with this disease. Since intestinal pathogens are important causes of reactive arthritis, and since cellular homing allows transport of bacterial products from the gut to synovium, we have approached the etiology of rheumatoid arthritis from this point of view. A series of observations has led to a hypothesis that patients with rheumatoid arthritis might favour, for genetic reasons, intestinal bacteria which are capable of inducing arthritis. In the long-run, with continuous seeding of bacterial products from the gut, the synovial inflammation is followed by erosion, exposition of cartilage antigens, and autoimmunity.

Influence of major histocompatibility complex on bacterial composition of fecal flora.

Very little is known about how the host genome influences the composition of the gastrointestinal flora, largely due to the great number and diversity of bacteria present in the flora and the difficulties of using traditional methods of bacterial isolation and identification. We have approached the problem by studying bacterium-derived cellular fatty acids in the stool samples of six mouse strains congenic for the major histocompatibility complex (MHC). The results obtained indicate that the composition of the fecal flora is genetically regulated. In addition to undefined gene loci, MHC alone has a pronounced effect, since mice with different MHC in the same background have significantly different fecal floras. Demonstration of the genetic influence on the gastrointestinal flora opens a new approach to studying the pathogenesis of bacterially induced diseases.

Characterisation of Eubacterium cell wall: peptidoglycan structure determines arthritogenicity.

OBJECTIVE: To elucidate factors involved in the arthritogenicity of bacterial cell walls. METHODS: For characterisation of an arthritogenic Eubacterium aerofaciens cell wall, peptidoglycan-polysaccharide (PG-PS) polymers were isolated by removing cell wall associated proteins (CWPs), PG and PS moieties were separated, and an attempt was made to de-O-acetylate PG-PS. The cell wall of E limosum was used as a non-arthritogenic control. The chemical composition of these cell wall preparations was analysed by gas chromatography-mass spectrometry. Also, their ability to resist lysozyme degradation and to sustain experimental chronic arthritis was tested. RESULTS: The observations made with the cell wall of E aerofaciens, an anaerobic habitant of the human intestine, were compared with those reported from a pathogenic Streptococcus, showing that in both strains a complex consisting of PG-PS is required for the induction of chronic arthritis. The PS moiety most probably protects PG from enzyme degradation, allowing prolonged tissue persistence and leading to the chronic synovial inflammation. CWPs attached to PG-PS are not necessary for this function. O-Acetylation of PG, which is required for arthritogenicity of the streptococcal cell wall, seems not to be present in the arthritogenic E aerofaciens PG or only occurs to a small degree; attempts to de-O-acylate the E aerofaciens cell wall did not affect its arthritogenicity or lysozyme resistance. CONCLUSION: The results obtained indicate that the source of bacterial cell wall plays no part in the chemical or structural requirements for PG to induce chronic cell wall arthritis in the rats; the chemical structure of the PG moiety is decisive.

Bacterial PCR in the diagnosis of joint infection.

OBJECTIVES: To evaluate the value of broad range bacterial PCR in the diagnosis of joint infection and to find out if there are bacteria causing arthritis which are not cultivable by the present methods. METHODS: Polymerase chain reaction (PCR) with broad range bacterial primers and DNA sequencing (bacterial PCR) was used to analyse 154 synovial fluid (SF) samples from patients with different arthritic diseases. RESULTS: Bacterial DNA was detected in 18 SF samples, including samples from six patients with culture proven purulent arthritis, and from three patients with possible purulent arthritis. Three samples from patients with culture confirmed purulent arthritis remained negative in bacterial PCR. CONCLUSIONS: The results indicate that in the usual diagnostic laboratory setting bacterial PCR does not offer any obvious advantage over bacterial culture in the microbiological diagnosis of joint infection.

Cytokine production in arthritis susceptible and resistant rats: a study with arthritogenic and non-arthritogenic Lactobacillus cell walls.

The basis of the different susceptibility to bacterial cell wall-induced arthritis between Lewis and Fischer rats is unclear. Likewise, it is not known why cell walls of some species of Lactobacillus are arthritogenic and those of others are not. With these two questions in mind, we investigated the role of anti-inflammatory (interleukin (IL)-10, IL-4) and proinflammatory (tumour necrosis factor (TNF)-alpha, IL-1 beta) cytokines in Lewis and Fischer rats injected intraperitoneally with cell walls from arthritogenic or nonarthritogenic species of Lactobacillus. Cytokine levels in the serum and in vitro production by peritoneal macrophages and splenocytes were studied. The results obtained indicate that the differences in the production of IL-10, IL-4, TNF-alpha or IL-1 beta do not explain the difference in the arthritis susceptibility between Lewis and Fischer rats. Likewise, the arthritogenicity of different Lactobacillus cell walls appears not to be dependent on their capacity to stimulate cytokine production.

Study of murine faecal microflora by cellular fatty acid analysis; effect of age and mouse strain.

Analysis of bacteria-derived cellular fatty acids was applied to study differences in faecal floras of inbred mice. The bacterial composition of the faecal flora clearly changes with age, whereas the sex does not affect it. Most interestingly, different mouse strains were found to have different faecal floras. This was particularly observed at the age of 17-19 weeks for stool samples of four different mouse strains; the mice were handled identically in identical environments, and the two congenic strains used were different from each other only by the major histocompatibility complex (MHC). These results suggest that composition of the faecal flora is genetically regulated.

BPI-ANCA is found in reactive arthritis caused by Yersinia and Salmonella infection and recognise exclusively the C-terminal part of the BPI molecule.

OBJECTIVE: To examine the prevalence, binding sites and functional interactions of antineutrophil cytoplasmic autoantibodies (ANCA) against the bactericidal/permeability increasing protein (BPI) in reactive arthritis (ReA). METHODS: Sera were analysed for the occurrence of ANCA by indirect immunofluorescence microscopy (IIF) and ELISA. Binding sites were determined using BPI, lipopolysaccharid binding protein (LBP), and fusion proteins of both proteins in ELISA. In addition, the effect of antibodies on the antibiotic activity of BPI was examined. RESULTS: BPI-ANCA was found in patients with Yersinia- and Salmonella-triggered ReA and directed against the C-terminal portion of BPI. Goat anti BPI antibodies recognising this part inhibited the antibiotic activity of BPI in vitro. CONCLUSION: BPI-ANCA was associated with ReA triggered by Salmonella and Yersinia infection. Directed against the C-terminal part of BPI, it can potentially inhibit its antibiotic activity and might be useful to identify patients with infectious bowel disease prone to extraintestinal sequelae.