Baseline serum levels of IgA anti-cyclic citrullinated protein antibodies in early rheumatoid arthritis predict radiographic progression after 11 years of treatment: a secondary analysis of the CIMESTRA study.

OBJECTIVE: Smoking and periodontitis are risk factors for developing rheumatoid arthritis (RA), suggesting a break of tolerance on mucosal surfaces. Immunoglobulin A (IgA) antibodies are part of the mucosal immune system. The dominant autoantibodies in RA are anti-cyclic citrullinated protein antibodies (ACPAs), and IgG and IgA subclasses exist simultaneously. This study aimed to investigate the association of ACPA IgA subtypes with disease activity and long-term radiographic outcomes in RA, compared with ACPA IgG. METHOD: Total ACPA IgG, IgA, IgA1, and IgA2 were quantified in serum from patients with early RA (n = 97). Patient characteristics, IgM rheumatoid factor (IgM-RF) status, clinical and biochemical disease activity scores, and radiographic status evaluated by total Sharp score (TSS), were assessed at baseline and after 2 and 11 years of treatment. RESULTS: All patients with ACPA IgA also had ACPA IgG. ACPA IgA positivity was associated with IgM-RF and male gender. Both ACPA IgA and IgG levels at baseline were weakly associated with disease activity markers. Baseline ACPA IgA and IgG did not show a linear correlation with radiographic status after 10 years, but could predict radiographic progression (ΔTSS ≥ 5 from 0 to 11 years), with positive likelihood ratios of 3.7 and 4.0, respectively. CONCLUSION: ACPA IgA and IgG were weakly associated with disease activity in early RA. RA patients with a ΔTSS ≥ 5 after 11 years of treatment had higher ACPA IgG and ACPA IgA levels at baseline; however, none of the ACPA subtypes was superior in predicting long-term radiographic progression.

Molecular dynamics calculation of molecular volumes and volumes of activation.

Experimentally, the effects of pressure on reaction rates are described by their pressure derivatives, known as volumes of activation. Transition state theory directly links activation volumes to partial molar volumes of reactants and transition states. We discuss a molecular dynamics method for the accurate calculation of molecular volumes, within which the volumes of molecular species are obtained as a difference between the volumes of pure solvent and solvent with a single molecule inserted. The volumes thus obtained depend on the molecular geometry, the strength and type of the solute-solvent interactions, as well as temperature and pressure. The partial molar volumes calculated using this approach agree well with experimental data. Since this method can also be applied to transition state species, it allows for quantitative analysis of experimental volumes of activation in terms of structural parameters of the corresponding transition states. The efficiency of the approach is illustrated by calculation of volumes of activation for three nonpolar reactions in nonpolar solvents. The results agree well with the experimental data.

The HealthNuts population-based study of paediatric food allergy: validity, safety and acceptability.

BACKGROUND: The incidence of hospital admissions for food allergy-related anaphylaxis in Australia has increased, in line with world-wide trends. However, a valid measure of food allergy prevalence and risk factor data from a population-based study is still lacking. OBJECTIVE: To describe the study design and methods used to recruit infants from a population for skin prick testing and oral food challenges, and the use of preliminary data to investigate the extent to which the study sample is representative of the target population. METHODS: The study sampling frame design comprises 12-month-old infants presenting for routine scheduled vaccination at immunization clinics in Melbourne, Australia. We compared demographic features of participating families to population summary statistics from the Victorian Perinatal census database, and administered a survey to those non-responders who chose not to participate in the study. RESULTS: Study design proved acceptable to the community with good uptake (response rate 73.4%), with 2171 participants recruited. Demographic information on the study population mirrored the Victorian population with most the population parameters measured falling within our confidence intervals (CI). Use of a non-responder questionnaire revealed that a higher proportion of infants who declined to participate (non-responders) were already eating and tolerating peanuts, than those agreeing to participate (54.4%; 95% CI 50.8, 58.0 vs. 27.4%; 95% CI 25.5, 29.3 among participants). CONCLUSION: A high proportion of individuals approached in a community setting participated in a food allergy study. The study population differed from the eligible sample in relation to family history of allergy and prior consumption and peanut tolerance, providing some insights into the internal validity of the sample. The study exhibited external validity on general demographics to all births in Victoria.

[Atrial sensing with fixed and floating electrodes at identical activities]. / Atriale Signalwahrnehmung mit wandständigen Elektroden und Floatingelektroden bei identischen Belastungen.

Despite advantages of single-lead VDD systems, the frequency of implantation of these pacemakers in patients with symptomatic atrioventricular block and normal sinus rhythm continues to decline. Therefore, data comparing the atrial sensing performance of floating and fixed electrodes at identical activities are rare. The aim of the study was to investigate atrial sensing via floating and fixed atrial electrodes at identical activity levels (supine position, left side position, seated position, hyperventilation, standing, walking, fast walking, walking up and down stairs, for 1.5 min each) by beat-to-beat analysis in 24 h Holter ECG. A total of 42 patients were included in the study (22 patients with a DDD system; 20 patients with a VDD system). In 45% of the DDD systems and only in 20% of the VDD systems an intermittent atrial undersensing during activity was recorded (p = 0.0024). The intermittent atrial undersensing in both groups was detected significantly more often in the first 15 s of an activity (p < 0.001). Floating sensing reduced the frequency of atrial undersensing in the initial phase of the activity significantly compared to atrial sensing by a fixed electrode (p = 0.0347). This advantage of floating electrodes and the significant earlier atrial signal recognition by floating electrodes might be useful in future DDD pacemakers by combining a VDD electrode with a fixed atrial electrode.

Evaluation of particle uptake in human blood monocyte-derived cells in vitro. Does phagocytosis activity of dendritic cells measure up with macrophages?

This work focuses on microparticles as potential antigen delivery systems to target professional antigen-presenting cells. Surface modified polystyrene microparticles were administered to human-derived macrophages (MPhis) and dendritic cells (DCs) in vitro to evaluate the phagocytosis activity of each cell type. To discriminate between internalised particles and those closely attached to the outside of the cells, particle internalisation was verified by confocal laser scanning microscopy. Especially positively charged particles tend to stick to the outer cell membrane and may lead to false positive results when measured by conventional microscopy. In contrast, fluorescence microscopy in combination with an extracellular fluorescence quenching agent (trypan blue) allows the unequivocal assessment of particle uptake for screening purposes. For this assay, the fluorescent label needs to be in direct contact to the quenching agent and cannot be localised inside the particle core. Different types of microparticles varying in size, surface-material and zeta potential resulted in vast differences regarding their uptake by MPhis and DCs as well as the maturation of DCs. Negatively-charged carboxylated and bovine serum albumin-coated particles were phagocytosed by MPhis to a relatively small extent. Interestingly, phagocytosis of these particles was still significantly lower in DCs while positively charged poly-L-lysine (PLL) coated particles induced high phagocytosis activity in both cell types. By comparing our results with literature data, we conclude that phagocytosis activity of DCs and MPhis largely depends on particle size and surface charge and is also influenced by the character of bulk and coating material. PLL can be directed to DCs and MPhis with comparable efficiency and, in addition, induce maturation of DCs.

Hydrophilic poly(DL-lactide-co-glycolide) microspheres for the delivery of DNA to human-derived macrophages and dendritic cells.

Biodegradable poly(lactide-co-glycolide) (PLGA) microspheres have a proven track record for drug delivery and are suggested to be ideal carrier systems to target therapeutics into phagocytic cells such as macrophages (MPhis) and dendritic cells (DCs). Microspheres prepared by spray-drying from different PLGA-type polymers were evaluated regarding their effect on phagocytosis, intracellular degradation and viability of human-derived macrophages MPhis and DCs. Even the microspheres prepared from the most hydrophilic polymer RG502H, were efficiently phagocytosed by primary human MPhis and DCs. Interestingly, uptake of PLGA microspheres by DCs as potent immune modulator cells was almost as efficient as uptake by the highly phagocytic MPhis. Phagocytosed microspheres remained inside the cells until decay with none of the microsphere preparations induced significant apoptosis or necrotic cell death. Acidic pH and the phagosomal environment inside the cells enhanced microsphere decay and release of encapsulated material. Degradation of microspheres consisting of the most hydrophilic PLGA polymer RG502H occurred in a reasonable time frame of less than 2 weeks ensuring the release of encapsulated drug during the life span of the cells. To explore important technical and biological aspects of DNA microencapsulation, we have studied DNA loading and in vitro DNA release of microspheres from different PLGA type polymers. Hydrophobicity and molecular weight of the PLGA polymers had profound influence on both the encapsulation efficiency of DNA and its release kinetics in vitro: the hydrophilic polymers showed higher encapsulation efficiency and faster release of intact DNA compared to the hydrophobic ones. These results suggest that microspheres from the PLGA polymer RG502H have improved characteristics for DNA delivery to human MPhis and DCs.

The effect of working tip angulation on root substance removal using Er:YAG laser radiation: an in vitro study.

OBJECTIVES: The present investigation attempted to determine the amount of cementum and/or dentin removal with Er:YAG laser radiation, dependent on the angulation of a specially-developed application tip. MATERIAL AND METHODS: Subject of the study were 150 extracted incisors, canines, premolars, and molars. Source of laser radiation was an Er:YAG laser device emitting pulsed infrared radiation at a wavelength of 2.94 microm with a pulse duration of 250 micros and a pulse repetition rate of 10 pps. The samples of the 3 study groups were irradiated with 380 laser pulses at radiation energies of 60 mJ (group A), 100 mJ (group B), or 180 mJ (group C). In each group, 10 samples were treated at working tip angulations of 15 degrees , 30 degrees , 45 degrees , 60 degrees , and 90 degrees. The substance removal was determined 3-dimensionally using a newly developed laser scanning system (100,000 surface points per sample, accuracy 5 microm) and a special image-analysing software (Match 3D). Statistical analysis was completed with ANOVA followed by multiple comparisons using the Scheffé-test and with linear regression analysis according to Pearson-Bravais (p < 0.05). RESULTS: Strong dependence of substance removal, both determined as maximum depth of the defects (0.5% quantil) as well as defect volume, on the angulation of the working tip was shown. At 60 mJ, the depth of the defects was 41.39 (+/- 32.55) microm at an angulation of 15 degrees and that at 90 degrees was 181.39 (+/- 74.42) microm (R2= 0.921). For the radiation energy at 100 mJ, the depth of the defects ranged from 51.96 (+/- 26.86) microm at 15 degrees to 306.64 (+/- 62.44) microm at 90 degrees (R2 = 0.983). Choosing radiation energies at 180 mJ, the depth of the defects ranged from 64.73 (+/- 27.73) microm at 15 degrees to 639.89 (+/- 47.28) microm at 90 degrees , on average (R2 = 0.853). CONCLUSIONS: The results of the present study provide clear evidence that besides the physical radiation parameters, also the parameters of clinical handling, in particular the angulation of the application tip, has a strong influence on the amount of root substance removal using Er:YAG laser radiation.

Comparison of multiobjective evolutionary algorithms: empirical results.

In this paper, we provide a systematic comparison of various evolutionary approaches to multiobjective optimization using six carefully chosen test functions. Each test function involves a particular feature that is known to cause difficulty in the evolutionary optimization process, mainly in converging to the Pareto-optimal front (e.g., multimodality and deception). By investigating these different problem features separately, it is possible to predict the kind of problems to which a certain technique is or is not well suited. However, in contrast to what was suspected beforehand, the experimental results indicate a hierarchy of the algorithms under consideration. Furthermore, the emerging effects are evidence that the suggested test functions provide sufficient complexity to compare multiobjective optimizers. Finally, elitism is shown to be an important factor for improving evolutionary multiobjective search.

Possible mechanisms for sensitivity to organophosphorus and carbamate insecticides in eastern screech-owls and American kestrels.

Effects of a single dietary exposure to fenthion and carbofuran on the survival, feeding behavior and brain ChE activity of eastern screech-owls, Otus asio and American kestrels, Falco sparverius, were evaluated. Birds were exposed to fenthion (23.6-189.0 ppm) or carbofuran (31.7-253.6 ppm) via meatballs. Carbofuran-exposed owls ate either < or = 10% or > or = 80% of the meatball whereas all kestrels ate < or = 10% of the meatball before exhibiting acute signs of toxicity. Fenthion-exposed owls and kestrels displayed a wide spectrum of meatball consumption (< 10-100%). Significant brain ChE inhibition was observed in dead and surviving kestrels exposed to fenthion and carbofuran and dead owls exposed to fenthion (P < 0.0001). Brain ChE activity of owls exposed to carbofuran that survived was not different from that of controls (P = 0.25). Data suggest: (1) slow feeding on a carbamate-contaminated item may provide limited protection from the toxicity of the chemical at certain rates of exposure; (2) the degree of ChE inhibition at neuromuscular junctions may be critical in determining the sensitivity of a species to a carbamate insecticide; (3) sensitivity may be a function of the ChE affinity for the carbamate inhibitor; and (4) the importance of neuromuscular junction ChE depression in determining the sensitivity of an animal may be species-specific.