Sublingual tolerance induction with antigen conjugated to cholera toxin B subunit induces Foxp3+CD25+CD4+ regulatory T cells and suppresses delayed-type hypersensitivity reactions.

Although sublingual (s.l.) immunotherapy with selected allergens is safe and often effective for treating patients with allergies, knowledge of the immunological mechanisms involved remains limited. Can s.l. administration of antigen (Ag) induce peripheral immunological tolerance and also suppress delayed-type hypersensitivity (DTH) responses? To what extent can s.l.-induced tolerance be explained by the generation of Foxp3+CD25+CD4+ regulatory T cells (T(reg))? This study addressed these questions in mice and compared the relative efficacy of administering ovalbumin (OVA) conjugated to cholera toxin B (CTB) subunit with administration of the same Ag alone. We found that s.l. administration of a single or even more efficiently three repeated 40-mug doses of OVA/CTB conjugate suppressed T-cell proliferative responses to OVA by cervical lymph node (CLN), mesenteric lymph node (MLN) and spleen cells and concurrently strongly increased the frequency of Ag-specific T(reg) in CLN, MLN and spleen and also transforming growth factor-beta (TGF-beta) levels in serum. The CLN and splenic cells from OVA/CTB-treated BALB/c mice efficiently suppressed OVA-specific T-cell receptor (TCR) transgenic (DO11.10) CD25-CD4+ effector T-cell proliferation in vitro. Further, s.l. treatment with OVA/CTB completely suppressed OVA-specific DTH responses in vivo and T-cell proliferative responses in mice immunized subcutaneously with OVA in Freund's complete adjuvant. The intracellular expression of Foxp3 was strongly increased in OVA-specific (KJ1-26+) CD4+ T cells from OVA/CTB-treated mice. Thus, s.l. administration of CTB-conjugated Ag can efficiently induce peripheral T-cell tolerance associated with strong increases in serum TGF-beta levels and in Ag-specific Foxp3+CD25+CD4+ T(reg) cells.

Experiences of threats and violence in the Swedish ambulance service.

Ambulance personnel often meet people in a crisis situation that requires a readiness to act, and which takes for granted a broad knowledge in caring, together with an ability to size up the circumstances in each separate incident. The afflicted individual's first contact with a medic in an emergency situation is very often ambulance personnel and this first meeting can involve incidents that may radically change the existing state of things for the ill or injured and, maybe, even for near relatives. Sometimes these situations can lead to threats and acts of violence aimed at the ambulance staff. The aim of the study was to describe how ambulance personnel perceive, how they are subjected to, and are influenced by, threats and violence in their day-to-day work. The empirical study was descriptive and consisted of a questionnaire comprising a total of 13 questions. Answers from the 66 respondents revealed that 53 persons (80.3%) were subjected to threats and/or violence. The majority were of the opinion that the relationship between the paramedic and the patient was most certainly affected when threat or violence is a part of the situation. The study shows that many ambulance personnel have, on occasion, been subjected to one or several threats and/or situations involving the use of violence. The majority regarded this as an unpleasant experience.

Measured lung dose correction factors for 50 MV photons.

Some clinically relevant measurements of lung tissue/water equivalent interfaces have been performed for a 50 MV therapeutic x-ray beam. The purpose was to investigate the severity of dose perturbation effects in lung tissue and adjacent tissues using an energy well above the common clinical practice in thoracic irradiations. The phantoms were constructed of solid water, PMMA and white polystyrene as soft tissue (water) equivalents, and cork was used as the lung tissue equivalent. Measurements were performed using radiographic film and a cylindrical ionization chamber. The results show that the degradation of the 20/80% beam penumbra in the lung region is severe, up to 2.5 times the penumbra in water for a 10 cm thick lung with a density of 0.30 x 10(3) kg m(-3). The lack of electronic equilibrium in the low-density region can cause underdosage at the lung/tumour interface of up to 30% of maximum target dose, and the build-up depth to 95% of target dose in unit density tissue behind the lung may be as large as 22 mm. It is also shown that these figures strongly depend on patient anatomy and beam size and why a careful calculation of the individual dose distribution is needed for optimal choice of photon beam energy in thoracic treatments.

Scanned intensity modulations for 50 MV photons.

Optimization of the dose distributions by individual beam compensation is a useful tool in conformal radiation therapy. Intensity modulation by electromagnetic scanning of a narrow elementary beam allows fast dose delivery and causes little change in beam quality compared with other methods, especially for high energies such as 50 MV. Intensity modulated beams from the MM50 accelerator were measured and compared with calculations based on Monte Carlo simulations. Good agreement between measurements and calculations were found, typically within 1% for central dose profiles. The steepest wedge angle that was produced with the scanning beam technique was of 45 degrees or 3.5% cm(-1) for a 20 cm x 20 cm field, slightly varying with depth. The elementary 50 MV photon 'pencil beam' for a full range, high-z bremsstrahlung target, is a wide dose distribution at 10 cm depth in water which limits the modulation gradient and hence the complexity of the modulation by the scanning of a photon pencil beam only. Scanned wedge beam distributions were modelled in the treatment planning system and a pelvic treatment with three fields was used to illustrate a clinical application. The resulting dose volume data were compared for different radiation qualities but with similar beam portals. 'Energy modulation' by field matching with lower photon energies was performed to sharpen the penumbra towards organs at risk.

Isolated unilateral hypoglossal neuropathy caused by dural arteriovenous fistula.

We report a case of isolated hypoglossal nerve paralysis caused by a dural arteriovenous fistula. Diagnosis is discussed with emphasis on conventional and MR angiography. The anatomy of the hypoglossal nerve is reviewed along with more common causes of pathologic conditions.

Test procedures for verification of an electron pencil beam algorithm implemented for treatment planning.

The calculation of an electron dose distribution in a patient is a difficult problem because of the presence of tissue and surface inhomogeneities. Verification of the dose planning system is therefore essential. In this investigation, a novel method is used to evaluate a commercially available system (Helax-TMS), at electron energies between 10 and 50 MeV, both for a conventional treatment unit and an MLC-collimated scanned beam unit with a helium-filled treatment head. First, the experiments were designed to verify the local beam database and some fundamental characteristics of the electron beam calculations. Secondly, a number of generalised situations that would be encountered in the clinical treatment planning were evaluated oblique incidence, field shaping with multi-leaf collimator, bolus edges, and air cavities. Dose distributions in two generalised anatomical phantoms simulating a neck and a nose were also analysed. The results have, when so possible, been presented as the dose ratio within the 'flattened area' for dose profiles and down to the 'treatment depth' (80% dose level) for depth doses. In the penumbra region and in the dose fall-off region, the comparison has been represented by the distance deviation between calculated and measured dose profiles or depth doses. A new tool, 'volume integration', was used to evaluate the deviations from a more clinical point of view. Most results were within +/- 2% in dose for volumes larger than a sphere with a diameter of 15 mm, or +/- 2 mm in position. Dose deviations were generally found for oblique incidences and below heterogeneities such as small air cavities and bolus edges in limited volumes.

Repeatability of airway deposition and tracheobronchial clearance rate over three days in chronic bronchitis.

Previous investigations on tracheobronchial clearance in chronic bronchitis or chronic obstructive pulmonary disease (COPD) have usually referred to measurements during a short time-period, i.e. a few hours. The purpose of this study, therefore, was to study regional particle deposition and tracheobronchial clearance during 72 h. In 14 patients with chronic bronchitis clearance of 111In-labelled 3.6 micrograms Teflon particles and lung function were measured on two occasions, with an interval of 2 weeks. Lung retention of test particles was measured at 0, 24, 48 and 72 h using a profile scanner. The weight of expectorated sputum samples was measured after the two clearance measurements. The particle retentions at all time-points were reproducible, as seen from the two measurements ( r > 0.90). The fast clearance phase was completed within 72 h. No correlation between sputum volume and clearance was seen. There was a significant negative correlation between airway resistance and the 72 h retention (r= -0.66), and an even better correlation between specific airway resistance and the 72 h retention (r = -0.82), indicating more central deposition in obstructed airways. There was no significant correlation between lung function tests reflecting smaller airways and the 72 h retentions. Deposition data agreed well with theoretical calculations and experimental data in healthy subjects. In spite of earlier findings that mucociliary transport is usually severely impaired in chronic bronchitis and COPD, the present results indicate that overall tracheobronchial mucus clearance in these patients is fairly effective, probably due to a productive cough. Alveolar deposition may be estimated by measurements of the 72 h retention in subjects with chronic obstructive pulmonary disease. The 72 h retention is dependent mainly on the calibre of larger airways. The present method of studying airway clearance during 3 days is highly reproducible.

Monoclonal anti-T cell (T12) antibody treatment of graft-versus-host disease in severe combined immunodeficiency: targeting of antibody and activation of complement on CD8+ cytotoxic T cell surfaces.

We report a 6-month-old male child with severe combined immunodeficiency who received an unirradiated blood transfusion and developed acute, severe graft-versus-host disease (GVHD), for which he received monoclonal anti-T cell (anti-T12) antibody treatment. The GVHD was manifested by a confluent maculopapular rash and increased liver function tests and was documented by skin biopsy. Separation of peripheral blood mononuclear cells forming rosettes with sheep red blood cells revealed engrafted T cells having the nonrelated HLA type of the blood donor. The patient was treated with intravenous monoclonal anti-T12 in a dose of 0.3 mg/kg/day for 5 days. An in vivo effect of the anti-T12 was suggested by clinical improvement of his skin rash and return of the liver transaminases to the normal range. Moreover, human complement components, activated C3 and C4, were detected by fluorescence microscopy on the surfaces of the engrafted CD8+ lymphocytes on the skin biopsy specimens. Also, with a biotin-avadin assay, the presence of the anti-T12 was detected on these same cells. These studies document not only the in vivo targeting of monoclonal anti-T12 antibody to cytotoxic T cells producing GVHD but also the activation of complement on these cells.