Prevention of delayed cerebral vasospasm by continuous intrathecal infusion of glyceroltrinitrate and nimodipine in the rabbit model in vivo

Objective: Intrathecal bolus administration of nitric oxide donors and calcium channel antagonists has been proposed to reduce cerebral vasospasm (CVS) in animal subarachnoid hemorrhage (SAH) models. Intrathecal continuous administration of these substances for CVS prevention has not been extensively evaluated. This study compared the efficacy of continuous intrathecal infusions of the NO donor glyceroltrinitrate and nimodipine in preventing delayed CVS associated with SAH in an animal model in vivo. Methods: New Zealand White rabbits were randomly assigned to six groups: no SAH/NaCl, no SAH/NO, no SAH/nimodipine, SAH/NaCl, SAH/NO, or SAH/nimodipine. Glyceroltrinitrate (GTN) at 0.5 μg/μl (0.5 μl/h) or nimodipine at 0.2 μg/μl (10 μl/h) or NaCl was continuously infused into the cisterna magna via an Alzet osmotic pump from day0 to day5 after injection of 1.0 ml autologous blood. The magnitude of spasm in the basilar artery was determined by comparison of pre- and posttreatment angiography and was calculated as proportional change in intraluminal diameter based on automatic measurements. Results: Atotal of 55 experiments and 110 angiograms were performed. SAH was associated with vasoconstriction of the basilar artery (SAH/NaCl group 19.85 ± 2.94%). Continuous intrathecal injection of GTN and nimodipine prevented SAH-induced CVS. There was significant prevention of CVS in animals treated with GTN (SAH/NO group 5.93 ± 5.2%, n = 11) and nimodipine (SAH/nimodipine group: 0.55 ± 2.66%, n = 9). There was no significant difference between the treatment groups and controls in prevention of CVS. Conclusions: This study demonstrates that prophylactic continuous intrathecal administration of either GTN or nimodipine equally prevents SAH-associated CVS in an animal mode

Evaluation of a Novel Rapid Test System for the Detection of Specific IgE to Hymenoptera Venoms

Background. The Allergy Lateral Flow Assay (ALFA) is a novel rapid assay for the detection of sIgE to allergens. The objective of this study is the evaluation of ALFA for the detection of sIgE to bee venom (BV) and wasp venom (WV) in insect venom allergic patients. Methods. Specific IgE to BV and WV was analyzed by ALFA, ALLERG-O-LIQ, and ImmunoCAP in 80 insect venom allergic patients and 60 control sera. Sensitivity and specificity of ALFA and correlation of ALFA and ImmunoCAP results were calculated. Results. The sensitivity/specificity of ALFA to the diagnosis was 100%/83% for BV and 82%/97% for WV. For insect venom allergic patients, the Spearman correlation coefficient for ALFA versus ImmunoCAP was 0.79 for BV and 0.80 for WV. However, significant differences in the negative control groups were observed. Conclusion. ALFA represents a simple, robust, and reliable tool for the rapid detection of sIgE to insect venoms

Continuous intrathecal glyceryl trinitrate prevents delayed cerebral vasospasm in the single-SAH rabbit model in vivo

Background: Delayed cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is a major cause of high morbidity and mortality. The reduced availability of nitric oxide (NO) in blood and cerebrospinal fluid (CSF) is well established as a key mechanism of vasospasm. Systemic administration of glyceryl trinitrate (GTN), an NO donor also known as nitroglycerin, has failed to be established in clinical settings to prevent vasospasm because of its adverse effects, particularly hypotension. The purpose of this study was to analyze the effect of intrathecally administered GTN on vasospasm after experimental SAH in the rabbit basilar artery. Methods: A single-hemorrhage model of SAH in rabbits was used to induce vasospasm. GTN (0.5mg/ml) or saline was infused via a subcutaneous implanted osmotic pump with continuous drug release into the cerebellomedullary cistern over 5days. The degree of vasospasm in the basilar artery was recorded with angiography on day 5 after SAH and was compared to baseline angiography on day 0. Findings: Significant reduction of basilar artery diameter was observed in the SAH group with saline infusion compared to sham-operated animals. Intrathecally administered GTN had no effect on the vessel diameter in sham-operated animals, whereas it significantly prevented vasospasm in the SAH group. Intrathecal GTN infusion did not affect arterial blood pressure. Conclusions: Prophylactic, continuous intrathecal administration of GTN prevents vasospasm of the basilar artery in the rabbit SAH model. No toxic effects could be demonstrated in this study. The clinical safety and feasibility of this strategy need to be further investigate

Context Dependent Role of Type 2 Innate Lymphoid Cells in Allergic Skin Inflammation.

The discovery of innate lymphoid cells (ILC) has profoundly influenced the understanding of innate and adaptive immune crosstalk in health and disease. ILC and T cells share developmental and functional characteristics such as the lineage-specifying transcription factors and effector cytokines, but importantly ILC do not display rearranged antigen-specific receptors. Similar to T cells ILC are subdivided into 3 different helper-like subtypes, namely ILC1-3, and a killer-like subtype comprising natural killer (NK) cells. Increasing evidence supports the physiological relevance of ILC, e.g., in wound healing and defense against parasites, as well as their pathogenic role in allergy, inflammatory bowel diseases or psoriasis. Group 2 ILC have been attributed to the pathogenesis of allergic diseases like asthma and atopic dermatitis. Other inflammatory skin diseases such as allergic contact dermatitis are profoundly shaped by inflammatory NK cells. This article reviews the role of ILC in allergic skin diseases with a major focus on ILC2. While group 2 ILC are suggested to contribute to the pathogenesis of type 2 dominated inflammation as seen in atopic dermatitis, we have shown that lack of ILC2 in type 1 dominated contact hypersensitivity results in enhanced inflammation, suggesting a regulatory role of ILC2 in this context. We provide a concept of how ILC2 may influence context dependent the mutual counterbalance between type I and type II immune responses in allergic skin diseases

Analysis of filaggrin mutations and expression in corneal specimens from patients with or without atopic dermatitis

BACKGROUND: Filaggrin is expressed in the epidermis and is essential for the maintenance of the epidermal barrier. Null mutations within the filaggrin gene (FLG) lead to a disturbed epidermal barrier and are associated with a significantly increased risk of atopic dermatitis (AD). The association of AD with ocular surface disorders prompted us to speculate that common FLG mutations may be particularly prevalent in AD patients with ocular comorbidities. METHODS: Corneal buttons and biopsies from AD patients with ocular involvement (n = 11) and from non-atopic patients (n = 9) with a histological diagnosis of keratitis were included in the study. DNA samples obtained from paraffin-embedded corneal specimens were genotyped for the two most common FLG mutations (R501X and 2282del4). Filaggrin protein expression was analysed by immunohistochemistry. RESULTS: Normal skin and corneal specimens (n = 6) were positive for filaggrin, which could be detected in the stratum corneum of the skin and in the basal epithelial layer of the cornea. Interestingly, all AD corneal specimens as well as the specimens from keratitis patients without AD were negative for filaggrin expression. Genotyping of the FLG mutations R501X and 2282del4 revealed wild-type alleles in all analysed samples. CONCLUSIONS: The lack of filaggrin expression observed in the analysed corneal specimens from AD patients is not due to the two most common FLG mutations (R501X, 2282del4) but is most likely secondary to inflammation, as all keratitis specimens of non-AD patients showed lack of filaggrin expression as well

Fliessgewässertemperatur - zwei Modellansätze für zukünftige Prognosen

Seit Längerem steigt die globale Durchschnittstemperatur der Atmosphäre und führt damit auch in der Schweiz zu einem Anstieg der Gewässertemperaturen. Verlässliche längerfristige Prognosen hierfür sind in der Schweiz auf Bundesebene zum jetzigen Zeitpunkt nicht erstellbar. Nun wurden an der Ecole Polytechnique Fédérale de Lausanne (EPFL) zwei Modellvarianten entwickelt, um längerfristig Antworten auf Fragestellungen bezüglich Temperaturentwicklung von Fliessgewässern in der Schweiz zu ermöglichen. Parallel dazu wurde ein modulares deterministisches Modell auf der Basis des räumlich verteilten Schneedeckenmodells Alpine3D der WSL/SLF erstellt

Epidemiological trends in mortality, event rates and case fatality of acute myocardial infarction from 2004 to 2015: results from the KORA MI registry

AIM: This study examines epidemiological trends of acute myocardial infarction (AMI) in Germany from 2004–2015 across different age groups, using data of the population-based KORA myocardial infarction registry. METHODS: Annual age-standardised, age-group- and sex-specific mortality and event rates (incident and recurrent) per 100,000 population as well as 28-day case fatality were calculated from all registered cases of AMI and coronary heart disease deaths in 25–74-year-olds from 2004–2015 and 75–84-year-olds from 2009–2015. Average annual percentage changes (AAPC) were calculated by joinpoint regression. RESULTS: Mortality rates declined considerably among the elderly (75–84 years), in men by –6.0% annually, due to declines of case fatality by –3.0% and incidence rate by 3.4% and in women by –10.0%, driven by declines in incidence (–9.1%) and recurrence rate (–4.9%). Significant mortality declines also occurred in males, 65–74 years of age (AAPC –3.8%). Among the age groups 25–54 years and 55–64 years, there was no substantial decline in mortality, event rates or case fatality except for a decline of incidence rate in 55–64-year-old men (AAPC –1.8%). CONCLUSION: Inhomogeneous AMI trends across age-groups indicate progress in prevention and treatment for the population >64 years, while among <55-year-olds, we found no significant trend in AMI morbidity and mortality. KEY MESSAGES: Age standardised AMI mortality continued to decline from 2009 to 2015 in the study region. Declines in AMI mortality were driven by declines in event rates (both incidence and recurrence rates) and case fatality. AMI trends were inconsistent across different age groups with the strongest declines in mortality and event rates among the elderly population (75–84 years of age)

Pollen allergens do not come alone: pollen associated lipid mediators (PALMS) shift the human immue systems towards a TH2-dominated response

Pollen allergy is characterized by a TH2-biased immune response to pollen-derived allergens. However, pollen-exposed epithelia do not encounter pure allergen but rather a plethora of protein and non-protein substances. We demonstrated that pollen liberate lipids with chemical and functional similarities to leukotriens and prostaglandins - the pollen associated lipid mediators (PALMs). To date, two main groups of PALMs have been characterized: The immunostimulatory PALMs activating innate immune cells such as neutrophils and eosinophils, and the immunomodulatory E1-phytoprostanes blocking IL-12 production of dendritic cells, resulting in the preferential induction of TH2 responses. This article reviews our work in the field of PALMs and their effects on cells of the innate and adoptive immune system. From recent results a general picture starts to emerge in which PALMs (and possibly other pollen-associated substances) may - independently from protein allergens - propagate an overall TH2 favoring micromilieu in pollen exposed tissue of predisposed individuals

The Bcl10–Malt1 complex segregates FcɛRI-mediated nuclear factor κB activation and cytokine production from mast cell degranulation

Mast cells are pivotal effector cells in IgE-mediated allergic inflammatory diseases. Central for mast cell activation are signals from the IgE receptor FcɛRI, which induce cell degranulation with the release of preformed mediators and de novo synthesis of proinflammatory leukotrienes and cytokines. How these individual mast cell responses are differentially controlled is still unresolved. We identify B cell lymphoma 10 (Bcl10) and mucosa-associated lymphoid tissue 1 (Malt1) as novel key regulators of mast cell signaling. Mice deficient for either protein display severely impaired IgE-dependent late phase anaphylactic reactions. Mast cells from these animals neither activate nuclear factor κB (NF-κB) nor produce tumor necrosis factor α or interleukin 6 upon FcɛRI ligation even though proximal signaling, degranulation, and leukotriene secretion are normal. Thus, Bcl10 and Malt1 are essential positive mediators of FcɛRI-dependent mast cell activation that selectively uncouple NF-κB–induced proinflammatory cytokine production from degranulation and leukotriene synthesis