Meta-analysis of ACE inhibitor-induced angioedema identifies novel risk locus.

BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.

Establishment of the deuterium oxide dilution method as a new possibility for determining the transendothelial water permeability.

Increase in transendothelial water permeability is an essential etiological factor in a variety of diseases like edema and shock. Despite the high clinical relevance, there has been no precise method to detect transendothelial water flow until now. The deuterium oxide (D2O) dilution method, already established for measuring transepithelial water transport, was used to precisely determine the transendothelial water permeability. It detected appropriate transendothelial water flow induced by different hydrostatic forces. This was shown in four different endothelial cell types. The general experimental setup was verified by gravimetry and absorbance spectroscopy. Determination of transendothelial electrical resistance (TEER) and immunocytochemical staining for proteins of the cell-cell contacts were performed to ensure that no damage to the endothelium occurred because of the measurements. Furthermore, endothelial barrier function was modulated. Measurement of transendothelial water flux was verified by measuring the TEER, the apparent permeability coefficient and the electrical capacity. The barrier-promoting substances cyclic adenosine monophosphate and iloprost reduced TEER and electrical capacity and increased permeability. This was accompanied by a reduced transendothelial water flux. In contrast, the barrier-damaging substances thrombin, histamine and bradykinin reduced TEER and electrical capacity, but increased permeability. Here, an increased water flow was shown. This newly established in vitro method for direct measurement of transendothelial water permeability was verified as a highly precise technique in various assays. The use of patient-specific endothelial cells enables individualized precision medicine in the context of basic edema research, for example regarding the development of barrier-protective pharmaceuticals.

Lipid levels in a cohort of healthy Danish schoolchildren ages 5 to 17 years.

It is internationally recognized to use clinical decision limits (CDL) when interpreting the lipid levels in both adults and children, even though the evidence for children is scarce. The purpose of this study is to describe how lipid levels progress in healthy Danish children ages 5 to 17 years. This study is based on the Childhood Health, Activity, and Motor Performance School Study Denmark (CHAMPS-study DK) consisting of 1456 observations of schoolchildren aged 5 to 17 years. Participants have been tested for blood levels of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, and remnant cholesterol levels are calculated. Finally, sex-specific percentile reference curves are presented. Percentile reference curves stratified by sex were generated for all cholesterols and showed that the total cholesterol level peaks at 4.32 mmol/l in 10-year-old boys and 4.46 mmol/l in nine-year-old girls. HDL levels in boys peak at 1.72 mmol/l in nine-year-old boys. HDL levels in girls and LDL levels in both sexes are nearly constant. Triglycerides kept rising to the age of 17 years in both sexes and remnant cholesterol decreased from age 5 to 17 years in both sexes. BMI z-score adjustment revealed no significant association with total cholesterol in both sexes but a significant association between HDL, LDL, triglycerides, and remnant cholesterol. This study is the first to generate percentile reference curves for blood levels of total cholesterol, LDL, HDL, triglycerides, and remnant cholesterol in a cohort of healthy Danish children aged 5 to 17 years.

The HLA ligandome of oropharyngeal squamous cell carcinomas reveals shared tumour-exclusive peptides for semi-personalised vaccination.

BACKGROUND: The immune peptidome of OPSCC has not previously been studied. Cancer-antigen specific vaccination may improve clinical outcome and efficacy of immune checkpoint inhibitors such as PD1/PD-L1 antibodies. METHODS: Mapping of the OPSCC HLA ligandome was performed by mass spectrometry (MS) based analysis of naturally presented HLA ligands isolated from tumour tissue samples (n = 40) using immunoaffinity purification. The cohort included 22 HPV-positive (primarily HPV-16) and 18 HPV-negative samples. A benign reference dataset comprised of the HLA ligandomes of benign haematological and tissue datasets was used to identify tumour-associated antigens. RESULTS: MS analysis led to the identification of naturally HLA-presented peptides in OPSCC tumour tissue. In total, 22,769 peptides from 9485 source proteins were detected on HLA class I. For HLA class II, 15,203 peptides from 4634 source proteins were discovered. By comparative profiling against the benign HLA ligandomic datasets, 29 OPSCC-associated HLA class I ligands covering 11 different HLA allotypes and nine HLA class II ligands were selected to create a peptide warehouse. CONCLUSION: Tumour-associated peptides are HLA-presented on the cell surfaces of OPSCCs. The established warehouse of OPSCC-associated peptides can be used for downstream immunogenicity testing and peptide-based immunotherapy in (semi)personalised strategies.

Efficacy of human C1 esterase inhibitor concentrate for treatment of ACE-inhibitor induced angioedema.

BACKGROUND: ACE inhibitor (ACEi) induced angioedema predominantly affects the upper aerodigestive tract. As ACEi induced angioedema is mediated by bradykinin, therapeutic response to antihistamines and glucocorticoids remains unsatisfactory. In bradykinin mediated hereditary angioedema, C1-esterase inhibitor (C1INH) is an effective and approved treatment since many years. Our aim was to evaluate the therapeutic effect of C1INH in ACEi induced angioedema. METHODS: We performed a double-blind, parallel-group, multicentre randomised placebo-controlled trial between December 2013 and September 2018. Eligible were adults with ACEi induced angioedema with airway obstruction. Participants were randomised 1:1 to single doses of either C1INH (20 IU/kg) or placebo (0.9% NaCl) i.v in addition to standard care (i.v. 500 mg prednisolone and 2.68 mg clemastine) i.v. Composite symptom scores were assessed at baseline and up to 48 h, at discharge and 1 week after discharge. Physician assessed time to complete oedema resolution (TCER) and time to onset of relief (TOR). RESULTS: 30 patients (16 C1INH, 14 placebo) were randomised and dosed. 25 (9 C1INH, 12 placebo) completed the study. TCER was 29.63 h ± 15.56 h in the C1INH and 17.29 h ± 10.40 h in the placebo arm (p = 0.0457). TORs were 4.13 h ± 3.38 h and 2.86 h ± 1.29 h for C1INH and placebo, respectively (p = 0.4443). There were no adverse events related to study medication. CONCLUSIONS: In the context of baseline application of steroids and antihistamines C1INH was inferior in the treatment of ACEi induced angioedema when compared to placebo with respect to time to complete resolution of symptoms. Eudra-CT Number: 2012-001670-28.

New Year's Eve in otorhinolaryngology: a 16-year retrospective evaluation.

PURPOSE: Pyrotechnics are a long-standing tradition at the turn of the year. There are little data available on New Year's Eve-associated ORL injuries. Due to restrictions during the Corona pandemic, the handling of fireworks and meetings on New Year's Eve 2020-2022 had been significantly changed. Our aim was to analyze first data about New Year's Eve-associated ORL injuries. METHODS: A retrospective analysis of 16 turns of the year (2006-2022) at a University ORL department was performed. The 2 recent years were influenced by the changes and restrictions of the COVID-19 pandemic. RESULTS: Of 343 emergency presentations, 69 presented with New Year's Eve-associated reasons (20%). 72% were male, 15.9% were underage. 74% presented for fireworks-related injuries, 19% due to violent altercations. Noise trauma was present in 71%. The average number of New Year's Eve-associated emergency patients per year and the average total number of patients were reduced by more than half under COVID-19 pandemic conditions. CONCLUSIONS: New Year's Eve-associated ORL injuries range from inner ear trauma to midface fractures. Long-term damage may include hearing loss and tinnitus. These results shall support the responsible use of fireworks even after the end of the special regulations of the COVID-19 pandemic.

Influence of Bruton's Tyrosine Kinase (BTK) on Epithelial-Mesenchymal Transition (EMT) Processes and Cancer Stem Cell (CSC) Enrichment in Head and Neck Squamous Cell Carcinoma (HNSCC).

Constitutively active kinases play a crucial role in carcinogenesis, and their inhibition is a common target for molecular tumor therapy. We recently discovered the expression of two oncogenic isoforms of Bruton's Tyrosine Kinase (BTK) in head and neck squamous cell carcinoma (HNSCC), Btk-p80 and BTK-p65. However, the precise role of BTK in HNSCC remains unclear. Analyses of a tissue microarray containing benign and malignant as well as inflammatory tissue samples of the head and neck region revealed the preferential expression of BTK-p80 in malignant tissue, whereas BTK-p65 expression was confirmed in over 80% of analyzed metastatic head and neck tumor cases. Therefore, processes associated with metastasis, like cancer stem cell (CSC) enrichment and the epithelial-mesenchymal transition (EMT), which in turn depend on an appropriate cytokine milieu, were analyzed. Treatment of HNSCC-derived cell lines cultured under 3D conditions with the BTK inhibitor AVL-292 caused reduced sphere formation, which was accompanied by reduced numbers of ALDH1A1+ CSCs as well as biological changes associated with the EMT. Moreover, we observed reduced NF-κB expression as well as altered NF-κB dependent pro-tumorigenic and EMT-associated cytokine release of IL-6, IFNγ, and TNFα when BTK activity was dampened. Therefore, an autocrine regulation of the oncogenic BTK-dependent process in HNSCC can be suggested, with BTK inhibition expected to be an effective treatment option for HNSCC.

Concomitant medication in patients with bradykinin-mediated angioedema - there's more than ACE inhibitors.

Bradykinin-mediated angioedema is a rare, non-allergic, potentially life-threatening disease. ACE inhibitor-induced angioedema and hereditary angioedema (HAE) are the two most common presentations. Therapeutic options, pathophysiology and diagnosis continue to be investigated, with considerable progress in HAE over the last few decades. For all patients with bradykinin-mediated angioedema, there are several medications that should be avoided or administered with caution. Some of the triggering medications are well known, while others are suspected or of unknown significance. A common denominator is that there is no approved therapy for bradykinin-mediated angioedema as a drug side effect. Some medications, such as tissue plasminogen activator, have a higher incidence of angioedema with potential airway compromise than ACE inhibitors, although this fact is widely underappreciated. In this review, we aim to summarize what is currently known and recommended about concomitant medication in HAE patients and the interaction of other bradykinin-influencing drugs.

[Epistaxis Requiring Intervention After Swab for SARS-CoV-2]. / Interventionsbedürftige Epistaxis nasi nach SARS-CoV-2-Abstrich.

INTRODUCTION: Since May 2020, the first nasopharyngeal POC tests for SARS-CoV-2 diagnostic have been available. Due to the long passage through the nasal cavity, there is a risk of injury with subsequent epistaxis. METHODS: We describe the course of disease of two female patients who suffered from massive epistaxis requiring intervention after an externally performed nasopharyngeal swab. RESULTS: After nasal tamponade, one patient underwent clipping of the sphenopalatine artery under general anesthesia. The other patient suffered from nasal bleeding with hemorrhagic shock requiring transfusion. She was intubated and admitted to our hospital. CONCLUSION: The nasopharyngeal swab for diagnosis of SARS-CoV-2 can lead to life-threatening complications in rare cases. Considering that daily more than 5 million corona tests are being carried out worldwide as part of the current pandemic, complications should not be neglected. It is necessary that the person performing the swab has a detailed understanding of the anatomy involved. Alternative test methods were further assessed with regard to their sensitivity. With regard to the future need for SARS-CoV-2 tests, alternative and lower-risk test procedures must be investigated and established.

Oral Plasma Kallikrein Inhibitor for Prophylaxis in Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is a life-threatening illness caused by mutations in the gene encoding C1 inhibitor (also called C1 esterase inhibitor) that lead to overactivation of the kallikrein-bradykinin cascade. BCX7353 is a potent oral small-molecule inhibitor of plasma kallikrein with a pharmacokinetic and pharmacodynamic profile that may help prevent angioedema attacks. METHODS: In this international, three-part, dose-ranging, placebo-controlled trial, we evaluated four doses of BCX7353 (62.5 mg, 125 mg, 250 mg, and 350 mg once daily) for the prevention of angioedema attacks over a 28-day period. Patients with type I or II hereditary angioedema with a history of at least two angioedema attacks per month were randomly assigned to BCX7353 or placebo. The primary efficacy end point was the number of confirmed angioedema attacks. Key secondary end points included angioedema attacks according to anatomical location and quality of life. RESULTS: A total of 77 patients underwent randomization, 75 received BCX7353 or placebo, and 72 completed the trial. The rate of confirmed angioedema attacks was significantly lower among patients who received BCX7353 at daily doses of 125 mg or more than among those who received placebo, with a 73.8% difference at 125 mg (P<0.001). Significant benefits with respect to quality-of-life scores were observed in the 125-mg and 250-mg dose groups (P<0.05). Gastrointestinal adverse events, predominantly of grade 1, were the most commonly reported adverse events, particularly in the two highest BCX7353 dose groups. CONCLUSIONS: Once-daily oral administration of BCX7353 at a dose of 125 mg or more resulted in a significantly lower rate of attacks of hereditary angioedema than placebo. Mild gastrointestinal symptoms were the principal side effect. (Funded by BioCryst Pharmaceuticals; APeX-1 ClinicalTrials.gov number, NCT02870972 .).

High-dose vitamin D during pregnancy and pathway gene polymorphisms in prevention of offspring persistent wheeze.

BACKGROUND: Randomized controlled trials (RCTs) suggest a protective effect of high-dose vitamin D supplementation in pregnancy on offspring risk of persistent wheeze, but only in some individuals, which might be explained by variations in vitamin D pathway genes. This study aimed to investigate the effect of vitamin D supplementation by maternal and offspring vitamin D receptor (VDR) genotype and GC genotype, encoding vitamin D binding protein (VDBP), in two RCTs. METHODS: In the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010 ) RCT, we analyzed the effect of high-dose vitamin D during pregnancy on the risk of persistent wheeze age 0-3 years by variants in single nucleotide polymorphisms (SNPs) in VDR (rs1544410, rs2228570, rs7975128, rs7975232) and GC (rs4588, rs7041). Replication was sought in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). RESULTS: In COPSAC2010 , VDR SNP rs1544410 influenced the effect of high-dose vitamin D: maternal Pinteraction  = .049 and child Pinteraction  = .001, with the largest effect in offspring from mothers with TT genotype: hazard ratio (95% CI), 0.26 (0.10-0.68), P = .006, and no effect among CT or CC genotypes: 0.85 (0.48-1.51), P = .58 and 0.94 (0.47-1.89), P = .87, respectively. However, these findings were not replicated in VDAART. There was no significant effect modification from maternal or offspring GC genotype in either COPSAC2010 or VDAART: all Pinteraction  ≥ .17. CONCLUSIONS: We found that the effect of high-dose vitamin D supplementation during pregnancy on offspring risk of persistent wheeze was significantly influenced by VDR genotype in the COPSAC2010 RCT, but not VDAART, which may be due to population differences.

Etiology and predictors of cluster attacks of hereditary angioedema that recur despite pharmaceutical treatment.

Introduction: Hereditary angioedema (HAE) is a disease that leads to recurrent swelling of the skin and mucous membranes, including the upper airway tract. Apart from being deadly, these attacks can be debilitating, which leads to a poor quality of life in patients. Clinicians are occasionally confronted with patients who have recurrent attacks despite treatment with C1 esterase inhibitor concentrate or ß2-receptor antagonists. The goal of this study was to investigate repeated attacks that occur 48 hours to 7 days ("cluster attacks") after treatment, to determine why they occur and the factors that may be associated with them, and thus to prevent their occurrence. Methods: We conducted a multicenter mixed retrospective-prospective study with data acquired from all documented attacks in our patients with collective (n = 132) between 2015 and 2018. Results: Eighty-five percent (n = 132) of our total patient collective (N = 156) agreed to participate in the study. Nine percent of these patients (n = 12) had cluster attacks, with a total of 48 cluster attacks. The data procured from the patients were mixed retrospective-prospective. Approximately 72% of all the cluster attacks were caused by exogenous stimuli (41% due to psychological stress, 29% due to physical stimuli, and 2% due to menstruation). Cluster attacks occurred in 7% of the patients who received prophylactic therapy in comparison with 12.5% of patients who received on-demand therapy. Cluster attacks comprised 48.4% of all the attacks that patients with cluster-attacks (n= 9) experienced. In addition, the patients who were underdosing their C1 esterase inhibitor treatment had cluster attacks more often. A lower "time to repeated attack" was seen in the patients who received on-demand therapy compared with those who received prophylactic therapy. Discussion: The percentage of the patients who had attacks as a result of exogenous triggers was higher in the cluster-attack group (70.5%) compared with the general HAE population (30-42%). Repeated attacks, therefore, were strongly associated with external triggers. The patients who received prophylactic treatment and who experienced cluster attacks were highly likely to have been underdosing, which may explain the repeated attacks despite treatment. In the patients prone to cluster attacks, prophylaxis should be considered.

Surgical tracheostomy in a cohort of COVID-19 patients.

BACKGROUND: One of the main symptoms of severe infection with the new coronavirus­2 (SARS-CoV-2) is hypoxemic respiratory failure because of viral pneumonia with the need for mechanical ventilation. Prolonged mechanical ventilation may require a tracheostomy, but the increased risk for contamination is a matter of considerable debate. OBJECTIVE: Evaluation of safety and effects of surgical tracheostomy on ventilation parameters and outcome in patients with COVID-19. STUDY DESIGN: Retrospective observational study between March 27 and May 18, 2020, in a single-center coronavirus disease-designated ICU at a tertiary care German hospital. PATIENTS: Patients with COVID-19 were treated with open surgical tracheostomy due to severe hypoxemic respiratory failure requiring mechanical ventilation. MEASUREMENTS: Clinical and ventilation data were obtained from medical records in a retrospective manner. RESULTS: A total of 18 patients with confirmed SARS-CoV­2 infection and surgical tracheostomy were analyzed. The age range was 42-87 years. All patients received open tracheostomy between 2-16 days after admission. Ventilation after tracheostomy was less invasive (reduction in PEAK and positive end-expiratory pressure [PEEP]) and lung compliance increased over time after tracheostomy. Also, sedative drugs could be reduced, and patients had a reduced need of norepinephrine to maintain hemodynamic stability. Six of 18 patients died. All surgical staff were equipped with N99-masks and facial shields or with powered air-purifying respirators (PAPR). CONCLUSION: Our data suggest that open surgical tracheostomy can be performed without severe complications in patients with COVID-19. Tracheostomy may reduce invasiveness of mechanical ventilation and the need for sedative drugs and norepinehprine. Recommendations for personal protective equipment (PPE) for surgical staff should be followed when PPE is available to avoid contamination of the personnel.

[Primary small cell neuroendocrine carcinoma of the larynx: a review of literature and case series]. / Kleinzelliges neuroendokrines Karzinom des Kopf-Hals-Bereichs: eine Übersichtsarbeit und Fallserie.

INTRODUCTION: Small cell neuroendocrine carcinoma (SCNC) of the larynx is a rare tumor entity with a 5-year overall survival (OS) of only 5 % after treatment with chemoradiotherapy. METHODS: A systematic review of the literature was performed for "SCNC" and "SCNC in head and neck". Our hospital's own electronic patient file database was investigated for patients diagnosed with a SCNC over the last 12 years. RESULTS: The effectiveness of chemoradiotherapy in SCNC is still unclear since randomized clinical trials are missing for the evaluation of standard of care treatment. Common therapy approaches are based on experiences with small cell lung cancer. 0.5 % of all SCNC occur in the head and neck region. In the last 12 years, we diagnosed 9 patients with SCNC, two of which were located in the larynx. Exemplarily, we report the case of a 29-year-old male with the initial diagnosis of a SCNC of the larynx with concurrent lymph node metastasis. This case is particularly interesting due to the young age at disease onset and the lack of major risk factors. Treatment was modified to nivolumab due to progressive disease after treatment with chemoradiotherapy. After an OS of 22 months, the patient deceased due to a tumor-associated major bleeding with airway obstruction. CONCLUSION: So far there are no clinical reports evaluating the use of nivolumab in third-line-therapy of SCNC. NTRK fusion (neurotrophic tyrosine receptor kinase gene fusion) or the folate receptor expression analysis should be considered to evaluate the potential use of a tropomyosin receptor kinase inhibitor or a folate receptor targeting therapy.

Adenosine receptor 2B activity promotes autonomous growth, migration as well as vascularization of head and neck squamous cell carcinoma cells.

Adenosine is a signaling molecule that exerts dual effects on tumor growth: while it inhibits immune cell function and thereby prevents surveillance by the immune system, it influences tumorigenesis directly via activation of adenosine receptors on tumor cells at the same time. However, the adenosine-mediated mechanisms affecting oncogenic processes particularly in head and neck squamous cell carcinomas (HNSCC) are not fully understood. Here, we investigated the role of adenosine receptor activity on HNSCC-derived cell lines. Targeting the adenosine receptor A2B (ADORA2B) on these cells with the inverse agonist/antagonist PSB-603 leads to inhibition of cell proliferation, transmigration as well as VEGFA secretion in vitro. At the molecular level, these effects were associated with cell cycle arrest as well as the induction of the apoptotic pathway. In addition, shRNA-mediated downmodulation of ADORA2B expression caused decreased proliferation. Moreover, in in vivo xenograft experiments, chemical and genetic abrogation of ADORA2B activity impaired tumor growth associated with decreased tumor vascularization. Together, our findings characterize ADORA2B as a crucial player in the maintenance of HNSCC and, therefore, as a potential therapeutic target for HNSCC treatment.

Adenosine-producing regulatory B cells in head and neck cancer.

BACKGROUND: Multiple mechanisms of immunosuppression have been identified in the tumor microenvironment including regulatory B cells (Breg). Recently, we have shown that Breg suppress T cell function by production of adenosine (ADO). However, the autocrine effect of ADO on B cells and the role of Breg in head and neck cancer remains unclear. METHODS: Blood (n = 42) and tumor tissue (n = 39) of head and neck cancer patients and healthy donors (n = 60) were analyzed by FACS. The effect of ADO on phenotype, intracellular signaling pathways, Ca2+ influx and ADO production was analyzed in Breg and effector B cells (Beff) by FACS, luminescence and mass spectrometry. The blockage of the ADO receptor A2A was analyzed in a murine head and neck cancer model. RESULTS: ADO-producing Breg were found in tumor tissue and peripheral blood. ADO inhibited the intracellular Bruton's tyrosine kinase (BTK) and Ca2+ influx only in Beff. The inhibition of BTK by ibrutinib mimicked the effect of ADO, and ibrutinib reduced the production of ADO by downregulation of CD39 in vitro. The inhibition of ADO receptor A2A significantly reduced tumor mass and increased B cell infiltration, in vivo. CONCLUSION: Our data demonstrate the presence of a novel ADO-producing Breg population within the tumor microenvironment in mice and humans. A new model is proposed on how ADO-producing Breg can influence the function of Beff cells in healthy donors and cancer patients. Thus, the modulation of the ADO pathway in B cells may serve as a therapeutic approach for cancer patients.

Bradykinin signaling regulates solute permeability and cellular junction organization in lymphatic endothelial cells.

OBJECTIVE: Determine the effect of bradykinin on solute permeability and cellular junctional proteins in human dermis microvascular endothelial cells. METHODS: Cells were characterized by immunofluorescence and fluorescence-activated cell sorting. Macromolecular transport of dextran and albumin was monitored. Junctional protein expression and phosphorylation were determined by immunoblot analyses. Intracellular calcium and cAMP levels were evaluated. Target gene expression at mRNA and protein levels was determined. RESULTS: Human dermis microvascular endothelial cells comprised 97% lymphatic endothelial cells. Bradykinin increased the permeability to dextran in a concentration-dependent manner, while reduced the permeability to albumin. Bradykinin treatment down-regulated VE-cadherin expression and affected its phosphorylation status at Tyr731. It also down-regulated claudin-5 expression at the transcriptional level through bradykinin-2-receptor signaling. An increase in the intracellular calcium levels and a reduction in the cAMP concentration were associated effects. Finally, bradykinin induced the up-regulation of vascular endothelial growth factor-C protein which was found increased in BK-induced human dermis microvascular endothelial cells culture supernates. CONCLUSIONS: Human dermis microvascular endothelial cells represent a model of lymphatic endothelial cells, in which bradykinin-2-receptor is expressed. Bradykinin-induced bradykinin-2-receptor signaling through intracellular calcium mobilization and reduction in cAMP levels, triggered changes in solute permeability and cellular junction expression. It further up-regulated vascular endothelial growth factors-C protein expression, which is a key modulator of lymphatic vessels function and lymphangiogenesis.

Prospective Analysis in Patients With HAE Under Prophylaxis With Lanadelumab: A Real-life Experience.

BACKGROUND AND OBJECTIVES: Patients with the rare disease hereditary angioedema (HAE) suffer from recurrent acute attacks of edema. There is no curative therapy, but the frequency of attacks and quality of life of severely affected patients can be improved by prophylactic therapy. The monoclonal antibody lanadelumab has been approved for routine prophylaxis in patients with HAE since November 2018. PATIENTS AND METHODS: In this prospective assessment, a long-term therapy with lanadelumab was initiated in 12 adult patients with HAE. We analyzed their course of disease 6 months after the start of long-term prophylactic therapy using a validated quality-of-life questionnaire and evaluated the frequency and severity of attacks as well as side effects. Furthermore, the therapy with lanadelumab was compared with the previous medication. RESULTS: To date, our study is the first prospective quality of life analysis in HAE patients under treatment with lanadelumab in real life conditions. Mean attack frequencies were reduced from 6.4 to 0.3 attacks per month and patient in our cohort (P<0.0001). No severe attacks occurred under lanadelumab prophylaxis. In all patients, quality of life increased significantly. CONCLUSIONS: Lanadelumab is an effective but expensive long-term prophylaxis for HAE patients. A favorable side-effect profile has been shown. J Drugs Dermatol. 2020;19(10):978-983. doi:10.36849/JDD.2020.5269.

The German debate on male circumcision and Habermas' model of post-secularity.

This paper considers Habermas' model of a post-secular political order in the light of the debate on male circumcision that arose in Germany after a court ruled that male circumcision was an unjustifiable act of bodily harm. Central to this model is the idea that religious reasons can only become effective in central legal institutions when they are translated into secular reasons. My paper demonstrates that there are two distinguishable readings of this proviso. On the one hand, there is a broad reading according to which it is only necessary to reach a conclusion that is in line with the democratic principle stating that all citizens can be regarded as co-legislators even if non-generalizable value orientations might then shape the interpretation of fundamental rights (in the case of circumcision, the right to bodily integrity). On the other hand, a truly secular (narrow) reading would avoid the inclusion of non-generalizable value orientations. The debate on circumcision demonstrates that these two interpretations lead to different and conflicting modes of justification. The broad reading allows for a justification of male circumcision, whereas the narrow reading makes such a justification unlikely. In addition, the filtering function of the proviso is weakened in a broad reading.

A randomized trial of icatibant in ACE-inhibitor-induced angioedema.

BACKGROUND: Angioedema induced by treatment with angiotensin-converting-enzyme (ACE) inhibitors accounts for one third of angioedema cases in the emergency room; it is usually manifested in the upper airway and the head and neck region. There is no approved treatment for this potentially life-threatening condition. METHODS: In this multicenter, double-blind, double-dummy, randomized phase 2 study, we assigned patients who had ACE-inhibitor-induced angioedema of the upper aerodigestive tract to treatment with 30 mg of subcutaneous icatibant, a selective bradykinin B2 receptor antagonist, or to the current off-label standard therapy consisting of intravenous prednisolone (500 mg) plus clemastine (2 mg). The primary efficacy end point was the median time to complete resolution of edema. RESULTS: All 27 patients in the per-protocol population had complete resolution of edema. The median time to complete resolution was 8.0 hours (interquartile range, 3.0 to 16.0) with icatibant as compared with 27.1 hours (interquartile range, 20.3 to 48.0) with standard therapy (P=0.002). Three patients receiving standard therapy required rescue intervention with icatibant and prednisolone; 1 patient required tracheotomy. Significantly more patients in the icatibant group than in the standard-therapy group had complete resolution of edema within 4 hours after treatment (5 of 13 vs. 0 of 14, P=0.02). The median time to the onset of symptom relief (according to a composite investigator-assessed symptom score) was significantly shorter with icatibant than with standard therapy (2.0 hours vs. 11.7 hours, P=0.03). The results were similar when patient-assessed symptom scores were used. CONCLUSIONS: Among patients with ACE-inhibitor-induced angioedema, the time to complete resolution of edema was significantly shorter with icatibant than with combination therapy with a glucocorticoid and an antihistamine. (Funded by Shire and the Federal Ministry of Education and Research of Germany; ClinicalTrials.gov number, NCT01154361.).