Specific immunotherapy prevents increased levels of allergen-specific IL-4- and IL-13-producing cells during pollen season

BACKGROUND: Specific allergen immunotherapy (SIT) is effective for treatment of IgE-mediated diseases: however, the mechanisms of action still remain unclear. Earlier, we showed that IL-4 and IL-13 are produced in response to specific allergens. The aim of this study was to investigate whether these cytokine responses were affected by allergen SIT, and, furthermore, to evaluate the effect of SIT on allergen-specific IgE and IgG4 levels. METHODS: Blood samples from pollen-sensitized individuals were collected before the pollen season (before treatment) and during the pollen season (after SIT or placebo treatment). Peripheral blood mononuclear cells were activated in vitro with allergens and the numbers of IL-4-, IL-13-, IL-10-, and IFN-gamma-producing cells were determined by ELISPOT. Serum levels of allergen-specific IgE and IgG4 were measured by RAST and ELISA, respectively. RESULTS: The numbers of IL-4- and IL-13-producing cells were shown to be increased in the placebo group during the pollen season, an increment which was absent in patients receiving allergen SIT. We found an increase in allergen-specific IgG4 in the SIT-treated individuals, but not in the placebo group. Both groups displayed elevated specific IgE levels during the pollen season. CONCLUSIONS: Taken together, our data show a downregulation of IL-4- and IL-13-producing cells in peripheral blood after SIT, suggesting induction of nonresponsiveness/tolerance or a redistribution of these cells. Furthermore, we demonstrate that SIT acts on antibody production by increasing the specific IgG4 levels.     

A modeling approach for compounds affecting body composition

Body composition and body mass are pivotal clinical endpoints in studies of welfare diseases. We present a combined effort of established and new mathematical models based on rigorous monitoring of energy intake (EI) and body mass in mice. Specifically, we parameterize a mechanistic turnover model based on the law of energy conservation coupled to a drug mechanism model. Key model variables are fat-free mass (FFM) and fat mass (FM), governed by EI and energy expenditure (EE). An empirical Forbes curve relating FFM to FM was derived experimentally for female C57BL/6 mice. The Forbes curve differs from a previously reported curve for male C57BL/6 mice, and we thoroughly analyse how the choice of Forbes curve impacts model predictions. The drug mechanism function acts on EI or EE, or both. Drug mechanism parameters (two to three parameters) and system parameters (up to six free parameters) could be estimated with good precision (coefficients of variation typically <20 % and not greater than 40 % in our analyses). Model simulations were done to predict the EE and FM change at different drug provocations in mice. In addition, we simulated body mass and FM changes at different drug provocations using a similar model for man. Surprisingly, model simulations indicate that an increase in EI (e.g. 10 %) was more efficient than an equal lowering of EI. Also, the relative change in body mass and FM is greater in man than in mouse at the same relative change in either EI or EE. We acknowledge that this assumes the same drug mechanism impact across the two species. A set of recommendations regarding the Forbes curve, vehicle control groups, dual action on EI and loss, and translational aspects are discussed. This quantitative approach significantly improves data interpretation, disease system understanding, safety assessment and translation across species.     

Knowledge of the patient as decision‐making power: staff members' perceptions of interprofessional collaboration in challenging situations in psychiatric inpatient care

Challenging situations in psychiatric inpatient settings call for interprofessional collaboration, but the roles and responsibilities held by members of different professions is unclear. The aim of this study was to describe staff members' perceptions of interprofessional collaboration in the context of challenging situations in psychiatric inpatient care. Prior to the study taking place, ethical approval was granted. Focus group interviews were conducted with 26 physicians, ward managers, psychiatric nurses, and nursing assistants. These interviews were then transcribed and analysed using qualitative content analysis. Results described participants' perceptions of shared responsibilities, profession‐specific responsibilities and professional approaches. In this, recognising knowledge of the patient as decision‐making power was understood to be a recurring theme. This is a delimited qualitative study that reflects the specific working conditions of the participants at the time the study was conducted. The findings suggest that nursing assistants are the most influential professionals due to their closeness to and first‐hand knowledge of patients. The results also point to the possibility of other professionals gaining influence by getting closer to patients and utilising their professional knowledge, thus contributing to a more person‐centred care.     

A new nanoemulsion formulation improves antileishmanial activity and reduces toxicity of amphotericin B

This work aimed to optimise a new nanoemulsion (NE) formulation loaded with Amphotericin B (AmB) and to evaluate its in vivo antileishmanial activity and in vitro haemolytic toxicity. The influence of gradual increases in pressure, using a high-pressure homogeniser, was evaluated. The NE was characterised for droplet size, polydispersity index, zeta potential and encapsulation efficiency (EE). For antileishmanial activity studies, AmB-NE was administered intravenously in mice infected by Leishmania infantum chagasi, which causes Visceral Leishmaniasis (VL). When the NE was submitted to gradual increases in pressure, the PI values and droplet size decreased. The droplet size (～145?nm) was lower than that obtained in previous studies. The zeta potential was negative and the EE was almost 100%. The haemolytic toxicity, evaluated on human red blood cells, for AmB-loaded NE was lower than that observed for the conventional AmB (C-AmB). C-AmB at 2?mg/kg was very toxic. In contrast, administration of the AmB-loaded NE, at same dose, did not result in any sign of acute toxicity, promoting a significant reduction in parasite burden as compared to the C-AmB. These findings suggest that this new AmB-loaded NE constitutes an attractive alternative for the treatment of VL due to improved efficacy and lower toxicity.     

Influence of age on reactivity to diverse emotional challenges in low- and high-anxiety rats

Studies have revealed that the extent of reactivity of high-anxiety rats to diverse challenges is different than low-anxiety rats and have provided important insights into the psychopathology of anxiety. Various factors intervene to allow defensive mechanisms to react to diverse threatening challenges, including ontogeny and the nature of the emotional challenge (e.g., conditioned vs. unconditioned). The present study investigated the extent to which a particular type of fear extrapolates to other emotional responses to diverse threatening challenges. Groups of 30- and 60-day-old rats were assigned to low freezing behavior (LFB) and high freezing behavior (HFB) groups using the contextual fear conditioning paradigm and subjected to either the fear-potentiated startle (FPS) test, novelty-induced ultrasound vocalizations (USVs) or elevated plus-maze (EPM) tests. At 30 days of age, HFB rats exhibited greater FPS than LFB rats. In contrast, prior selection of HFB and LFB did not affect the performance of 30-day-old animals in the EPM and novelty-induced USVs. Sixty-day-old animals exhibited a performance deficit in all three tests. These data suggest that the performance of young rats in animal models of anxiety parallels their selection as LFB and HFB in the contextual fear conditioning paradigm. However, the increased fear-like behavior exhibited by the 60-day-old HFB rats may elicit performance deficits in conditioned and unconditioned fear tests. These results suggest that the interaction between hyperanxiety and age may cause a performance deficit despite the animals’ increased fear-like behavior when facing emotional challenges, thus resembling psychiatric patients in many respects.     

Endoluminal Nd:YAG laser application in ex vivo biliary porcine tissue

Adequate biliary drainage with endoscopic or percutaneous placement of self-expandable metal stents represents the goal of palliation in patients with inoperable malignant obstruction of the biliary tree. As an adjunct to stenting, various tissue ablation treatments have been proposed with conflicting results. The aim of this study was to test the effect on biliary tissue of a new ablation technique based on Nd:YAG laser light delivery. The study was conducted on ex vivo specimens of 18 healthy farm pigs, using cystic ducts that are the simplest biliary structures to isolate and cannulate ex vivo. A 22G cannula was positioned into the cystic duct and a quartz optical fibre, with a prototypal cooling system, was inserted into the cannula. Nd:YAG laser output powers of 10, 12, and 15 W were tested, with a total delivered energy of 1000 J in continuous mode in each case. After laser treatment, histological analysis was performed. At macroscopical examination, no lesions of the external wall of the cystic ducts were detected. At histopathological examination, a coagulative necrosis involving the entire mucosa up to the muscolaris propria without significant changes of periductal tissues was observed in all specimens. This study shows the possibility of using Nd:YAG laser on ex vivo porcine biliary ducts with the effect of obtaining a coagulative necrosis involving the whole mucosa.     

Physical inactivity in patients with rheumatoid arthritis: data from twenty-one countries in a cross-sectional, international study

OBJECTIVE: Regular physical activity is associated with decreased morbidity and mortality. Traditionally, patients with rheumatoid arthritis (RA) have been advised to limit physical exercise. We studied the prevalence of physical activity and associations with demographic and disease-related variables in patients with RA from 21 countries. METHODS: The Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis (QUEST-RA) is a cross-sectional study that includes a self-report questionnaire and clinical assessment of nonselected consecutive outpatients with RA who are receiving usual clinical care. Frequency of physical exercise (>or=30 minutes with at least some shortness of breath, sweating) is queried with 4 response options: >or=3 times weekly, 1-2 times weekly, 1-2 times monthly, and no exercise. RESULTS: Between January 2005 and April 2007, a total of 5,235 patients from 58 sites in 21 countries were enrolled in QUEST-RA: 79% were women, >90% were white, mean age was 57 years, and mean disease duration was 11.6 years. Only 13.8% of all patients reported physical exercise>or=3 times weekly. The majority of the patients were physically inactive with no regular weekly exercise: >80% in 7 countries, 60-80% in 12 countries, and 45% and 29% in 2 countries, respectively. Physical inactivity was associated with female sex, older age, lower education, obesity, comorbidity, low functional capacity, and higher levels of disease activity, pain, and fatigue. CONCLUSION: In many countries, a low proportion of patients with RA exercise. These data may alert rheumatologists to motivate their patients to increase physical activity levels.