The central role of IL-33/IL-1RL1 pathway in asthma: From pathogenesis to intervention.

Interleukin-33 (IL-33), a member of the IL-1 family, and its cognate receptor, Interleukin-1 receptor like-1 (IL-1RL1 or ST2), are susceptibility genes for childhood asthma. In response to cellular damage, IL-33 is released from barrier tissues as an 'alarmin' to activate the innate immune response. IL-33 drives type 2 responses by inducing signalling through its receptor IL-1RL1 in several immune and structural cells, thereby leading to type 2 cytokine and chemokine production. IL-1RL1 gene transcript encodes different isoforms generated through alternative splicing. Its soluble isoform, IL-1RL1-a or sST2, acts as a decoy receptor by sequestering IL-33, thereby inhibiting IL1RL1-b/IL-33 signalling. IL-33 and its receptor IL-1RL1 are therefore considered as putative biomarkers or targets for pharmacological intervention in asthma. This review will provide an overview of the genetics and biology of the IL-33/IL-1RL1 pathway in the context of asthma pathogenesis. It will discuss the potential and complexities of targeting the cytokine or its receptor, how genetics or biomarkers may inform precision medicine for asthma targeting this pathway, and the possible positioning of therapeutics targeting IL-33 or its receptor in the expanding landscape of novel biologicals applied in asthma management.

[Experienced quality assurance in the IVOM structural contract of the AOK­BW : A practical example]. / Gelebte Qualitätssicherung im IVOM-Strukturvertrag der AOK­BW : Ein Praxisbeispiel.

BACKGROUND: According to § 73c of the Social Security Codebook V (SGB V), the AOK health insurance structural contract regulates the treatment of macular diseases by intravitreal drug administration (IVOM) in Baden-Württemberg (BW). Quality assurance is a central part of the agreement in order to ensure the high quality as well as effective and sufficient care of patients. MATERIAL AND METHODS: Every year at least 2% of the cases of the 254 currently participating surgeons are evaluated in a pseudonymized procedure by a panel of experts based on the billing data. Based on quality parameters, such as accuracy of diagnosis, quality and completeness of treatment documents and adherence to treatment pathways, the Medical Advisory Board recommends sanctions or facilitation of controls. The overall assessment of an expert opinion is based on a matrix of the evaluated quality parameters. The transmission of findings and expert opinions is digital and web based. Each surgeon has access to a comparative analysis of the quality data over time (benchmarking). RESULTS: In the first 11 quality assurance rounds, a total of 3639 expert opinions were made by a total of 20 reviewers. With respect to the quality parameter "diagnosis", the surgeon and the expert opinion differed in an average 7% of cases. Sanctions or facilitation of control by changing the sample were recommended 138 times for 80 surgeons in the first 10 quality assurance rounds. Financial sanctions or exclusion from contracts were each decided four times by the steering committee. DISCUSSION: The digital, web-based quality assurance system presented here within the framework of the IOVM structural contract of the AOK-BW should be perceived as an opportunity to classify and improve one's own quality level with respect to intravitreal treatment of retinal diseases. The current focus of quality assurance is on diagnosis and adherence to the disease-specific treatment recommendations of the professional societies. If the analysis of data could be extended to individual patient histories over time, quality assurance could be better used for questions of health services research.

Characterization of a lung epithelium specific E-cadherin knock-out model: Implications for obstructive lung pathology.

The airway epithelium regulates responses to aeroallergens, acting as a physical and immunological barrier. In asthma, epithelial barrier function and the expression of adherens junction protein E-cadherin is compromised, but it is unknown whether this is cause or consequence of the disease. We hypothesized that airway epithelial loss of E-cadherin is a critical step in the development of manifestations of asthma. We generated a transgenic mouse model with conditional loss of E-cadherin in lung epithelial cells at birth and onwards. We observed normal lung development at the time of birth in mice lacking E-cadherin in the lung epithelium. However, E-cadherin deficiency led to progressive epithelial damage in mice growing into adulthood, as evidenced by airway epithelial denudation, decreased zonula occludens (ZO)-1 expression, loss of ciliated cells, and enlarged alveolar spaces. In addition, spontaneous goblet cell metaplasia with mucus production was observed. These epithelial changes were accompanied by elevated levels of the epithelial-derived chemokine CCL17, infiltration of eosinophils and dendritic cells, and mucus production. In conclusion, loss of E-cadherin induces features in the lung reminiscent of those observed in asthma, indicating that the disruption of E-cadherin-mediated cell-cell contacts may play a key role in the development of asthma manifestations.

Subcutaneous immunotherapy suppresses Th2 inflammation and induces neutralizing antibodies, but sublingual immunotherapy suppresses airway hyperresponsiveness in grass pollen mouse models for allergic asthma.

BACKGROUND: Both subcutaneous and sublingual allergen immunotherapy (SCIT and SLIT) have been shown to effectively suppress allergic manifestations upon allergen exposure, providing long-term relief from symptoms in allergic disorders including allergic asthma. Clinical studies directly comparing SCIT and SLIT report a different kinetics and magnitude of immunological changes induced during treatment. Comparative studies into the mechanisms underlying immune suppression in SCIT and SLIT are lacking. OBJECTIVE: We aimed to establish an experimental model for grass pollen (GP) SCIT and SLIT that would allow a head-to-head comparison of the two treatments. METHODS: BALB/c mice were sensitized with GP extract, followed by SCIT and SLIT treatments with various GP dosages. Subsequently, we challenged mice with GP and measured airway responsiveness (AHR), GP-specific immunoglobulins, ear swelling tests (EST), eosinophilic inflammation in bronchoalveolar lavage fluid (BALF), and T cell cytokine release after restimulation of lung cells (IL-5, IL-10, and IL-13). RESULTS: We find that SLIT treatment was able to suppress allergen-induced AHR, while allergic inflammation was not effectively suppressed even at the highest GP dose in this model. In contrast, SCIT treatment induced higher levels of GP-specific IgG1, while SLIT was superior in inducing a GP-specific IgG2a response, which was associated with increased Th1 activity in lung tissue after SLIT, but not SCIT treatment. Interestingly, SCIT was able to suppress Th2-type cytokine production in lung cell suspensions, while SLIT failed to do so. CONCLUSIONS AND CLINICAL RELEVANCE: In conclusion, GP-SCIT suppresses Th2 inflammation and induced neutralizing antibodies, while GP-SLIT suppresses the clinically relevant lung function parameters in an asthma mouse model, indicating that the two application routes depend on partially divergent mechanisms of tolerance induction. Interestingly, these data mirror observations in clinical studies, underscoring the translational value of these mouse models.

Subcutaneous immunotherapy with purified Der p1 and 2 suppresses type 2 immunity in a murine asthma model.

BACKGROUND: Allergen-specific immunotherapy can induce long-term suppression of allergic symptoms, reduce medication use, and prevent exacerbations of allergic rhinitis and asthma. Current treatment is based on crude allergen extracts, which contain immunostimulatory components such as ß-glucans, chitins, and endotoxin. Use of purified or recombinant allergens might therefore increase efficacy of treatment. AIMS: Here, we test application of purified natural group 1 and 2 allergens from Dermatophagoides pteronyssinus (Der p) for subcutaneous immunotherapy (SCIT) treatment in a house dust mite (HDM)-driven mouse model of allergic asthma. MATERIALS AND METHODS: HDM-sensitized mice received SCIT with crude HDM extract, a mixture of purified Der p1 and 2 (DerP1/2), or placebo. Upon challenges, we measured specific immunoglobulin responses, allergen-induced ear swelling response (ESR), airway hyperresponsiveness (AHR), and inflammation in bronchoalveolar lavage fluid (BAL) and lung tissue. RESULTS: ESR measurement shows suppression of early allergic response in HDM-SCIT- and DerP1/2-SCIT-treated mice. Both HDM-SCIT and DerP1/2-SCIT are able to suppress AHR and eosinophilic inflammation. In contrast, only DerP1/2-SCIT is able to significantly suppress type 2 cytokines in lung tissue and BAL fluid. Moreover, DerP1/2-SCIT treatment is uniquely able suppress CCL20 and showed a trend toward suppression of IL-33, CCL17 and eotaxin levels in lung tissue. DISCUSSION: Taken together, these data show that purified DerP1/2-SCIT is able to not only suppress AHR and inflammation, but also has superior activity toward suppression of Th2 cells and HDM-induced activation of lung structural cells including airway epithelium. CONCLUSIONS: We postulate that treatment with purified natural major allergens derived from HDM will likely increase clinical efficacy of SCIT.

Biomimetic optimisation of branched fibre-reinforced composites in engineering by detailed analyses of biological concept generators.

The aim of this study is the biomimetic optimisation of branched fibre-reinforced composites based on the detailed analysis of biological concept generators. The methods include analyses of the functional morphology and biomechanics of arborescent monocotyledons and columnar cacti as well as measurements and modelling of mechanical properties of biomimetic fibre-reinforced composites. The key results show evidence of notch stress reduction by optimised stem-branch-attachment morphology in monocotyledons and columnar cacti. It could be shown that some of these highly interesting properties can be transferred into biomimetic fibre-reinforced composites.

Pim1 kinase activity preserves airway epithelial integrity upon house dust mite exposure.

Most patients with allergic asthma are sensitized to house dust mite (HDM). The allergenicity of HDM largely depends on disruption of the integrity and proinflammatory activation of the airway epithelium. In this study, we hypothesized that Pim1 kinase activity attenuates HDM-induced asthma by preserving airway epithelial integrity. The effects of Pim1 kinase activity on barrier function and release of the proinflammatory mediators IL-1α and CCL20 were studied in vitro in 16HBE and primary bronchial epithelial cells (PBECs). Pim1-proficient and -deficient mice were exposed to a HDM-driven model of allergic asthma, and airway hyperresponsiveness (AHR) was measured upon methacholine challenge. Airway inflammation and proinflammatory mediators in lung tissue and BAL fluid were determined. We observed that inhibition of Pim1 kinase prolongs the HDM-induced loss of barrier function in 16HBE cells and sensitizes PBECs to HDM-induced barrier dysfunction. Additionally, inhibition of Pim1 kinase increased the HDM-induced proinflammatory activity of 16HBE cells as measured by IL-1α secretion. In line herewith, HDM exposure induced an enhanced production of the proinflammatory chemokines CCL17 and CCL20 in Pim1-deficient mice compared with wild-type controls. While we observed a marked increase in eosinophilic and neutrophilic granulocytes as well as mucus cell metaplasia and AHR to methacholine in mice exposed to HDM, these parameters were independent of Pim1 kinase activity. In contrast, levels of the Th2-cytokines IL-5 and IL-10 were significantly augmented in HDM-treated Pim1-deficient mice. Taken together, our study shows that Pim1 kinase activity maintains airway epithelial integrity and protects against HDM-induced proinflammatory activation of the airway epithelium.

[Treatment of retinal arterial branch occlusion with transluminal Nd:YAG laser embolectomy]. / Behandlung retinaler Arterienastverschlüsse mittels transluminaler Nd:YAG-Laser-Embolektomie.

BACKGROUND: There is currently no effective therapy for retinal artery branch occlusion (RABO). Transluminal Nd:YAG embolectomy (TYE) was developed to achieve rapid reperfusion; however, it is still a subject of controversy. A Nd:YAG laser is focused on the occluded vessel, the vessel wall is ruptured and the embolism dislocates to the vitreous humor through the opening in the artery. METHOD: We retrospectively examined the results of five patients treated with TYE. RESULTS: The age of the patients was 26-75 years (mean age 58 years, median 68 years). Initial visual acuity was hand movements to 1.0 and all patients had visual field defects. Treatment was performed between 4 and 30 h from the onset of symptoms. Visual acuity improved markedly in two cases the next day (hand movements to 0.8 and 0.4 to 1.0) and final visual acuity was between 0.8 and 1.25. All treatments led to vitreous hemorrhage but only one patient required surgical treatment. The range of follow-up was 4-42 months. CONCLUSIONS: The results are in accordance with those published in the literature. It can be concluded that TYE is a fast, easy and readily available method that should be taken into account especially in cases with low initial visual acuity.

[Intravitreal injection. Drugs to treat subretinal hemorrhage]. / Intravitreale Injektionen. Medikamente bei subretinalen Blutungen.

Since 1996 acute subretinal hemorrhages have been treated by intravitreal injections. Large proteins injected into the vitreous cavity can cross the retina as well as the underlying retinal pigment epithelium. After intravitreal injection of tissue plasminogen activator (TPA), plasminogen, which is part of a subretinal clot, is converted to plasmin in the presence of fibrin. Plasmin is a relatively unspecific protease that liquefies a formed fibrin clot. Simultaneous intravitreal injection causes an inferior displacement of the liquefied hemorrhage. Beside mechanical effects on subretinal clots plasmin inhibits choroidal neovascularization by hydrolysis of the extracellular matrix as well as growth factors. After successful displacement of a subretinal hemorrhage an additional anti-VEGF (vascular endothelial growth factor) therapy is required.

Web-based training in German university eye hospitals - Education 2.0?

PURPOSE: To analyse web-based training in ophthalmology offered by German university eye hospitals. METHODS: In January 2010 the websites of all 36 German university hospitals were searched for information provided for visitors, students and doctors alike. We evaluated the offer in terms of quantity and quality. RESULTS: All websites could be accessed at the time of the study. 28 pages provided information for students and doctors, one page only for students, three exclusively for doctors. Four pages didn't offer any information for these target groups. The websites offered information on events like congresses or students curricular education, there were also material for download for these events or for other purposes. We found complex e-learning-platforms on 9 pages. These dealt with special ophthalmological topics in a didactic arrangement. In spite of the extensive possibilities offered by the technology of Web 2.0, many conceivable tools were only rarely made available. It was not always possible to determine if the information provided was up-to-date, very often the last actualization of the content was long ago. On one page the date for the last change was stated as 2004. CONCLUSION: Currently there are 9 functional e-learning-applications offered by German university eye hospitals. Two additional hospitals present links to a project of the German Ophthalmological Society. There was a considerable variation in quantity and quality. No website made use of crediting successful studying, e.g. with CME-points or OSCE-credits. All German university eye hospitals present themselves in the World Wide Web. However, the lack of modern, technical as well as didactical state-of-the-art learning applications is alarming as it leaves an essential medium of today's communication unused.

Bilateral congenital dacryocystocele as a cause of respiratory distress in a newborn.

Newborns with respiratory distress and nasal obstruction must be examined for congenital dacryocystocele. This disease is caused by a stenosis in the proximal and distal area of the nasolacrimal duct and leads to a cystic dilatation of this duct. A case of a newborn with bilateral dacryocystocele and dyspnoea is presented. The otorhinolaryngologic as well as the paediatric examination could only reveal in the rhinoscopic examination a tumor of the left nasal cavity that partly obstructed the endonasal space. No other pathologic findings were detected. To clarify the origin and the localization of the tumor as well as to exclude an intracranial relation, a magnetic resonance imaging of the middle face and the frontal skull base was performed. After probe and rinsing of the lacrimal ducts the symptoms improved rapidly. In newborns with nasal obstruction a bilateral rhinoscopy of the lower nasal meatus is required to exclude the existence of a dacryocystocele.

Exploiting current understanding of antibiotic action for discovery of new drugs.

The introduction of antibiotics for the chemotherapy of bacterial infections has been one of the most important medical achievements of the past 50 years. However, the emergence of bacterial resistance to antibiotics undermines the therapeutic utility of existing agents, creating a requirement for the discovery of new antibacterial drugs. Several drug discovery strategies have emerged, including incremental improvements to existing antibiotics by chemical manipulation and the search for novel drug targets based on genomic approaches. An alternative strategy seeks to exploit opportunities for drug discovery arising from an understanding of the mode of action of existing antibiotics. Thus biochemical pathways or processes inhibited by antibiotics already in clinical use may nevertheless contain key functions that represent unexploited targets for further drug discovery. A major benefit of employing pathways or processes that are already known to contain drug targets is that proof of principle for drug intervention is already established. This approach to drug discovery is illustrated by reviewing target sites for existing antibiotics and considering how this information might be applied for the discovery of new agents inhibiting peptidoglycan synthesis, tRNA synthesis, transcription and DNA replication.

Exploiting current understanding of antibiotic action for discovery of new drugs.

The introduction of antibiotics for the chemotherapy of bacterial infections has been one of the most important medical achievements of the past 50 years. However, the emergence of bacterial resistance to antibiotics undermines the therapeutic utility of existing agents, creating a requirement for the discovery of new antibacterial drugs. Several drug discovery strategies have emerged, including incremental improvements to existing antibiotics by chemical manipulation and the search for novel drug targets based on genomic approaches. An alternative strategy seeks to exploit opportunities for drug discovery arising from an understanding of the mode of action of existing antibiotics. Thus biochemical pathways or processes inhibited by antibiotics already in clinical use may nevertheless contain key functions that represent unexploited targets for further drug discovery. A major benefit of employing pathways or processes that are already known to contain drug targets is that proof of principle for drug intervention is already established. This approach to drug discovery is illustrated by reviewing target sites for existing antibiotics and considering how this information might be applied for the discovery of new agents inhibiting peptidoglycan synthesis, tRNA synthesis, transcription and DNA replication

[Population-based study of diabetic retinopathy in Wolfsburg]. / Populationsbezogene Erhebung zur diabetischen Retinopathie in Wolfsburg.

INTRODUCTION: Since November 1997 the complete documentation of an ophthalmological examination of diabetics has been annually subsidized by the Volkswagen Corporation Health Maintenance Organization (VW-HMO). METHODS: The results of an annual ophthalmological examination were recorded in a standardised history sheet developed by the Initiative Group for Early Detection of Diabetic Eye Diseases. These data included visual acuity, intraocular pressure, lens status and a description of fundus abnormalities. RESULTS: Within 26 months ophthalmological examinations of 2,801 patients were completed which represented 4.5% of all VW-HMO insured patients. On average, patients suffered from diabetes for 9.6 years (SD +/- 8.3), artificial intraocular lenses were present in 357 eyes (6.4%) and 1,216 eyes (12.0%) were diagnosed with cataract or posterior capsule opacification impairing visual acuity. Out of 263 patients younger than 40 years old, 18.8% had a mild or moderate and 3.3% a severe non-proliferative diabetic retinopathy (NPDR). A proliferative diabetic retinopathy (PDR) was found in 2.2% of the younger patients. Of 2,228 patients aged 40 years and older, 11.9% had a mild or moderate and 2.6% a severe NPDR. In 0.9% of this group PDR was diagnosed. CONCLUSIONS: An annual ophthalmological screening based on a survey sheet of the Initiative Group was successfully introduced. For the first time a population-based evaluation on the prevalence of diabetic retinopathy was carried out for inhabitants of a German city. The prevalence of PDR was found to be lower than previously published in comparable studied.

[Histopathology of 8 corneal buttons after penetrating keratoplasty in silicone oil-associated keratopathy]. / Histopathologie von 8 Hornhautexzisaten nach penetrierender Keratoplastik bei silikonöl-assoziierter Keratopathie.

BACKGROUND: In the literature there is only a limited number of morphological reports on clinically diagnosed silicone oil associated keratopathy describing different histological changes. The purpose of the present study was to evaluate the most common histopathological features of this disorder. MATERIAL AND METHODS: We reviewed the registry of the ophthalmopathological laboratory at the University of Marburg with respect to the following histopathological diagnoses: "bullous keratopathy", "endothelial-epithelial corneal decompensation", "band keratopathy" and "endothelial degeneration". These specimens were cross-checked with appropriate medical records. Eight specimens with a clinical diagnosis of silicone oil induced keratopathy were identified. All specimens were examined by light microscopy. RESULTS: Histologically, a long-standing bullous keratopathy was seen in 5 out of 8 specimens. A descemetocele was present in two other corneas. One case displayed band keratopathy. A posterior collagenous layer (PCL) between Descemet's membrane and the endothelium was identified in 7 out of 8 specimens examined. This layer was of a fibrillar type in 2 corneal buttons and of a fibrocellular type in all remaining specimens with PCL. PCL was associated with endothelial cell loss and degeneration. The endothelial cell density varied between 0 and 5 cells per high power field. CONCLUSION: Posterior collagenous layer associated with degenerating endothelium appears to be the most frequent histopathological feature in silicone oil induced keratopathy. The variety of PCL in this condition makes a firm histopathological diagnosis of "Silicone oil induced keratopathy" rather difficult.

Homodimerization of amyloid precursor protein and its implication in the amyloidogenic pathway of Alzheimer's disease.

We reported previously that the carbohydrate domain of the amyloid precursor protein is involved in amyloid precursor protein (APP)-APP interactions. Functional in vitro studies suggested that this interaction occurs through the collagen binding site of APP. The physiological significance remained unknown, because it is not understood whether and how APP dimerization occurs in vivo. Here we report that cellular APP exists as homodimers matching best with a two-site model. Consistent with our published crystallographic data, we show that a deletion of the entire sequence after the kunitz protease inhibitor domain did not abolish APP homodimerization, suggesting that two domains are critically involved but that neither is essential for homodimerization. Finally, we generated stabilized dimers by expressing mutant APP with a single cysteine in the ectodomain juxtamembrane region. Mutation of Lys(624) to cysteine produced approximately 6-8-fold more A beta than cells expressing normal APP. Our results suggest that amyloid A beta production can in principle be positively regulated by dimerization in vivo. We suggest that dimerization could be a physiologically important mechanism for regulating the proposed signal activity of APP.

[Physiological functional evaluation of retinal implants in animal models]. / Physiologische Funktionsprüfungen von Retinaimplantaten an Tiermodellen.

Retinal implants can--by electrical stimulation--create visual impressions in people with certain kinds of degenerative retinal diseases (e.g. Retinitis Pigmentosa). Electrically evoked potentials in the retina must be transferred into the visual cortex in an orderly manner, a prerequisite for any kind of form- and movement-perception. In the current developmental stage the difficult investigations are performed in various animal models: isolated retinae of intact chicken and of RCS-rats (a model for Retinitis Pigmentosa), as well as in anesthetised rabbits, pigs and cats with intact retinae. Our investigations show that spatially selective ganglion-cell responses can be recorded following focal electrical stimulation, in healthy and as well in degenerated retinae. Registration of activities in area 17 of the visual cortex demonstrate that electrical retinal stimulation can indeed activate it.

Ritonavir, efavirenz, and nelfinavir inhibit CYP2B6 activity in vitro: potential drug interactions with bupropion.

Since antiretroviral drugs are known to inhibit many cytochrome P450 isoforms, the inhibition of CYP2B6 by non-nucleoside reverse transcriptase inhibitors and viral protease inhibitors was studied in vitro in human liver microsomes using bupropion hydroxylation as the CYP2B6 index reaction. Mean IC(50) values (microM) for inhibition of bupropion hydroxylation were: nelfinavir (2.5), ritonavir (2.2), and efavirenz (5.5). The reaction was only weakly inhibited by indinavir, saquinavir, amprenavir, delavirdine, and nevirapine. The inhibition of bupropion hydroxylation in vitro by nelfinavir, ritonavir, and efavirenz indicates inhibitory potency versus CYP2B6 and suggests the potential for clinical drug interactions.