[Teaching pain management. An innovative curriculum model at the University of Witten/Herdecke (UWH)]. / Schmerztherapie in der Lehre. Ein innovatives Curriculumsmodell an der Universität Witten/Herdecke (UWH).

BACKGROUND: The subject of pain and pain therapy is not mandatory in medical curricula in Germany. Therefore, the German Society for the Study of Pain (DGSS) has developed a core-curriculum for pain and suggested its implementation for all medical faculties. METHOD: At the University of Witten/Herdecke this DGSS core curriculum was extended in terms of a "pain week", which comprised 22 h of seminars and clinical teaching and started in 2009. The knowledge gained by the students regarding the intended learning issues was measured by a pre-post self-assessment questionnaire. RESULTS: In almost every category the students reported significant knowledge gain. The learning issues were rated as relevant for the professional career. CONCLUSION: The "pain week" is intended to be a constant part of the medical curriculum at the University of Witten/Herdecke in the future. It will be integrated into the new cross-sectional subject of palliative care and be assessed by examinations.

Is a PBL curriculum a better nutrient medium for student-generated learning issues than a PBL island?

Problem based learning (PBL) is often introduced in curricula in form of short segments. In the literature the value of these PBL-islands is doubted. In order to gain more insight in this curricular approach, we compared student generated learning issues, from a 7-week PBL-island introduced in a traditional curriculum (PBL-I), with the gold standard of a PBL-based model-curriculum (PBL-B) existing in parallel at the same University (Ruhr-University Bochum, Germany). Both tracks use five identical PBL-cases. Thousand seven hundred and three student-generated learning issues of 252 tutorial groups (193 PBL-I and 59 PBL-B groups with six to seven students per group) were analysed in seven different categories. Results showed that overall there were no substantial differences between both curricula. PBL-B students generated more problem-related and less basic science clinical learning issues than PBL-I students, but in both groups learning issues were related to the same number of different subjects. Furthermore, students in the PBL-curriculum tend to generate little less but slightly better phrased issues. Taken together, we found no substantial evidence with respect to student-generated learning issues that could prove that students cannot work with the PBL-method, even if it is introduced later in the curriculum and last only for a short period of time.

Impaired virus-induced interferon-alpha2 release in adult asthmatic patients.

BACKGROUND: Interferon-alpha (IFN-alpha) not only serves as a first defence line of the immune system against viral attacks but also interacts with T-helper type 1 (Th1)/ T-helper type 2 (Th2) regulation and various other cell types like basophils and monocytes, thereby linking innate and acquired immunity. Recently, we demonstrated that children with allergic asthma produced significantly lower amounts of virus-induced IFN-alpha2 compared with healthy children or those with intrinsic asthma. OBJECTIVE: In this study, we extend our analysis to examine in a cohort study whether IFN-alpha2 is also reduced in allergic asthma of adults. METHODS: Adults with allergic asthma and healthy controls were prospectively recruited. Blood cultures were stimulated with different viruses (respiratory syncytial virus (RSV), newcastle disease virus (NDV)) and analysed for IFN-alpha2 protein release and gene transcription. RESULTS: Virus-induced IFN-alpha2 release from blood cells of allergic asthmatic patients was significantly reduced compared with healthy controls, independent of the virus used (NDV(asthma)=221+/-134 pg/mL, NDV(healthy)=555+/-341 pg/mL, P=0.003 and RSV(asthma)=46+/-27 pg/mL, RSV(healthy)=108+/-90 pg/mL, P=0.014). Values=mean+/-standard deviation). It was not influenced by medication, especially cortico-steroids. IFN-alpha2 mRNA expression 5 h after NDV stimulation confirmed the ELISA results and correlated well with release data (r=0.397, P=0.033). CONCLUSION: Like children, adults with allergic asthma show impaired virus-induced IFN-alpha2 release in whole blood, indicating a systemic phenomenon in patients with bronchial asthma and atopic phenotype. Impaired virus-induced IFN-alpha release could be a marker of inflammation in chronic allergic asthma.

Efficacy of sublingual swallow immunotherapy in children with severe grass pollen allergic symptoms: a double-blind placebo-controlled study.

BACKGROUND: Local application of allergen extracts in specific immunotherapy is accompanied by increased compliance and significantly reduced side effects. However, efficacy of local immunotherapy in children has yet not been sufficiently demonstrated. This study was performed to determine clinical efficacy of high dose sublingual swallow immunotherapy (SLIT) by a double-blind placebo-controlled study in children with grass pollen allergy using high dose allergen extracts. METHODS: A total of 161 children with seasonal rhinoconjunctivitis of which, 68 had also asthma symptoms were enrolled in a multicenter double-blind placebo-controlled study for 1 year and treated on a daily basis with sublingually applied allergen drops. After 1 year all children were given treatment for another 2 years in an open-controlled setting. Symptom scores and medication were assessed during the pollen seasons with structured interviews. Applied allergen dosage, compliance, and side effects were documented by daily diary cards. Primary endpoint was a clinical index (CI) combining symptom scores with medication index. Titrated skin prick tests (SPT) and specific antibody measurements were performed each year. RESULTS: Combining symptom with medication scores to CI was highly reliable (reliability coefficient = 0.89, standard error = 9.6%). Allergen-specific IgE- and IgG-subclass antibodies increased significantly in patients treated with SLIT indicating an activation of the immune response induced by the locally applied grass pollen extract. SPT reactivity did not change during therapy. After 1 year of SLIT in the original design we observed no significant difference in the CI between treatment and placebo analyzing all patients included in the study per intention to treat and per protocol. However, subgroup analysis in a repeated measures model revealed that patients with SLIT and severe symptoms before the beginning of treatment (CI > mean/ > 1.51) showed a significant improvement of clinical symptoms after 3 years. CONCLUSION: In this study SLIT was accompanied by a significant placebo effect. Efficacy of treatment could only be seen in children with severe clinical symptoms and this became clinically marked after 3 years of therapy.

Differential expression of IFN-alpha subtypes in human PBMC: evaluation of novel real-time PCR assays.

Studies of the human IFN-alpha subtype system have been hampered by the lack of efficient procedures to quantify and differentiate the expression of the highly homologous IFN-alpha subtypes. Here we evaluate four novel real-time PCR assays for the specific detection and quantification of IFN-alpha mRNA for the subtypes alpha(2), alpha(6), alpha(8) and alpha(1/13) in a combined assay in human peripheral blood mononuclear cells (PBMC). This included (a) the selection of beta-glucuronidase (GUS) as a suitable housekeeping gene for relative quantification; (b) verification of the specificity by using human DNA of different IFN-alpha subtypes; and (c) comparison of the amplification efficiencies among the different assays. This highly sensitive method allows the detection of low-level, constitutive IFN-alpha mRNA and shows differences in the composition of constitutive IFN-alpha subtypes compared to other cell types (HeLa and HEp-2). The in vitro stimulation of PBMC with Newcastle disease virus (NDV), Respiratory syncytial virus (RSV) or an inactivated Herpes simplex (HSV) preparation leads to the transcriptional induction of all IFN-alpha subtypes investigated but to different expression levels. Among the subtypes detected, IFN-alpha(13/1) and alpha(2) are the major transcripts followed by alpha(8), and finally alpha(6) as a minor transcribed subtype. Time-kinetics of IFN-alpha transcriptional activation also revealed variations in the course of IFN-alpha transcription between NDV, RSV or HSV. The data obtained from the real-time PCR assays correlated well with IFN-alpha(2) protein release. In conclusion, we have demonstrated the suitability and reliability of new real-time PCR assays for the rapid and efficient analysis of IFN-alpha subtype expression.

Monitoring allergen immunotherapy of pollen-allergic patients: the ratio of allergen-specific IgG4 to IgG1 correlates with clinical outcome.

BACKGROUND: Although allergen immunotherapy has been established as a treatment of type I allergy back in 1911, until now the underlying mechanisms have not been fully understood, nor are there any parameters which would allow one to monitor an ongoing treatment or to assess therapeutic success in the meantime. OBJECTIVE: We wanted to define allergen-specific parameters that change due to treatment in correlation with the clinical outcome. METHODS: We conducted a controlled study with grass pollen-allergic children and compared allergen-specific antibody titres before and 1 year after the onset of immunotherapy in contrast with untreated allergic and healthy children. Two recombinant forms of the major allergen group V of Phleum pratense (Phl p 5) served as model allergens. RESULTS: No change in IgE levels and no significant reduction of skin prick test (SPT) reactivity were seen. On the other hand, a significant reduction of symptom scores in the treated group and a significant rise in allergen-specific IgG1, IgG2 and IgG4 due to the treatment could be observed, but in neither case could we establish a correlation between the increasing amounts of the single antibody classes and the reduction of symptom scores. But most interestingly, when comparing the ratio of IgG4 to IgG1 with the symptom scores, we found significant correlations. Nevertheless, treated allergic patients still differ considerably from healthy controls as nonatopics have hardly any measurable allergen-specific IgG antibodies and no IgE antibodies at all. CONCLUSION: The ratio of IgG4 to IgG1 can serve as a valuable parameter that allows us to assess the success of immunotherapy already 1 year after the onset. The increase of specific IgG1 in relation to IgG4 during treatment reflects a possible influence of this subclass on the induction of tolerance towards allergens.

Allergenic activity of a major grass pollen allergen is elevated in the presence of nasal secretion.

Phl p5 is a major allergen of timothy grass and causes rhinitis and bronchial asthma in nearly all patients allergic to grass pollen. The biochemical processing of this molecule by the nasal mucosa at its first encounter and possible changes of its biologic activity are unknown. Two isoforms of the allergen were expressed in Escherichia coli and subsequently purified. Conversion of these preparations to various forms with molecular size between 10 and 20 kD in the presence of nasal secretion was observed. Surprisingly, in skin prick test assays with allergic patients the mixture of converted peptides caused significantly higher allergic response when compared with the parent protein. Allergenic activity of the recombinant N-terminal Phl p5a and the C-terminal Phl p5b as measured by skin prick test and histamine release assays was significantly higher than that of the respective parent molecules. Using pancreatic rather than nasal secretion, Phl p5b was completely degraded and its allergenicity was almost completely reduced. Proteolytic degradation converts Phl p5 to defined fragments with increased allergenicity. Complete degradation of Phl p5 on the mucosa could be a preventive strategy to destroy its potency for the induction of an allergic response.

Investigation of different recombinant isoforms of grass group-V allergens (timothy grass pollen) isolated by low-stringency cDNA hybridization--antibody binding capacity and allergenic activity.

A cDNA library of timothy grass pollen was screened for homologous isoforms of major group-V allergens by low stringency hybridization with a Phl p 5 (Phleum pratense) probe. After restriction analysis of the 40 clones obtained, 17 were selected for cDNA sequencing. Of these clones, two were unrelated to group-V allergens, six showed high similarity but an incomplete open reading frame and nine had high similarity with a complete open reading frame. Comparison of deduced amino acids of ten complete cDNA clones confirmed the presence of two major isoforms, a and b. Within these two subgroups, only minor sequence variations were observed. Eight isoforms were expressed in Escherichia coli K12 and purified to homogeneity. Although the subgroups a and b could be distinguished by their molecular masses and by binding constants towards monoclonal antibodies, all isoforms turned out to be biochemically similar. Ribonuclease activity as a marker for the biological function of group-V allergens was shown to be in the same range for both subgroups. Analysis of allergenic B-cell responses towards the isoforms in 26 grass pollen allergic patients revealed that the IgE reactivities to the different isoforms were identical for each individual. IgE reactivities and allergenic activities of three isovariants and an allergen of a different group were compared in a selected group of four grass pollen allergic patients by immunoblot, histamine-release and skin-prick tests. The IgE reactivity does not necessarily mirror the allergenic activity of the single molecule, and the variability of allergenic activity between the isovariants does not, in every case, depend on the structural differences of these allergens. We conclude that group-V isoallergens in grass pollen, although they can be structurally different, induce a similar B-cell response but can show variable allergenic activity. Thus, the most allergenic isoform of each important group of allergens should be sufficient for the diagnosis of type-I allergy. Whether the isoallergenic variation has any significant influence on the outcome of immunotherapy in allergic disease still has to be elucidated.