Granulomatosis with polyangiitis in a patient with polydipsia, facial nerve paralysis, and severe otologic complaints: a case report and review of the literature

Background: Granulomatosis with polyangiitis, formerly known as Wegener granulomatosis, is a necrotizing vasculitis with granulomatous inflammation that belongs to the class of antineutrophil cytoplasmic antibodies-positive diseases. It occurs in a localized and a systemic form and may present with a variety of symptoms. Involvement of the upper respiratory tract is very common, while neurologic, endocrinological, and nephrological dysfunction may occur. Case presentation: We describe the case of a 29-year-old Central European male patient presenting with severe bilateral sensorineural hearing loss, otorrhea, and one-sided facial nerve paralysis. The patient was unsuccessfully treated with i.v. antibiotics at another hospital in Berlin, and tympanic tubes were inserted. After presentation to our emergency room, he was hospitalized and further diagnostics started. Increased fluid intake and 12 kg weight gain over the last months were reported. The patient was diagnosed with granulomatosis with polyangiitis and diabetes insipidus. The patient's condition improved after treatment with rituximab. Discussion: A comprehensive PubMed search of all articles with granulomatosis with polyangiitis and diabetes insipidus was conducted to assess which combination of symptoms occurs simultaneously and whether other parts of the pituitary are commonly involved. The 39 selected articles, describing 61 patients, showed that ear-nose-throat involvement occurred most commonly, in 71% of cases. Of patients, 59% had involvement of the anterior pituitary gland, while true panhypopituitarism occurred in 13% of cases. Only one case report featured the same set of symptoms as described herein. Conclusion: Granulomatosis with polyangiitis is a highly variable disease, commonly involving the upper airways, but that may present with symptoms solely related to the pituitary gland. Clinicians should have a low threshold to investigate for granulomatosis with polyangiitis in patients with therapy-resistant otorrhea. Patients may present with a complex set of symptoms, and integrating different specialists when additional symptoms occur may lead to faster diagnosis

Risk assessment-led characterisation of the SiteChar UK North Sea site for the geological storage of CO2

Risk assessment-led characterisation of a site for the geological storage of CO2 in the UK northern North Sea was performed for the EU SiteChar research project as one of a portfolio of sites. Implementation and testing of the SiteChar project site characterisation workflow has produced a ‘dry-run’ storage permit application that is compliant with regulatory requirements. A site suitable for commercial-scale storage was characterised, compatible with current and future industrial carbon dioxide (CO2) sources in the northern UK. Pre-characterisation of the site, based on existing information acquired during hydrocarbon exploration and production, has been achieved from publicly available data. The project concept is to store captured CO2 at a rate of 5 Mt per year for 20 years in the Blake Oil Field and surrounding Captain Sandstone saline aquifer. This commercial-scale storage of 100 Mt CO2 can be achieved through a storage scenario combining injection of CO2 into the oil field and concurrent water production down-dip of the field. There would be no encroachment of supercritical phase CO2 for more than two kilometres beyond the field boundary and no adverse influence on operating hydrocarbon fields provided there is pressure management. Components of a storage permit application for the site are presented, developed as far as possible within a research project. Characterisation and technical investigations were guided by an initial assessment of perceived risks to the prospective site and a need to provide the information required for the storage permit application. The emphasis throughout was to reduce risks and uncertainty on the subsurface containment of stored CO2, particularly with respect to site technical performance, monitoring and regulatory issues, and effects on other resources. The results of selected risk assessment-led site characterisation investigations and the subsequent risk reassessments are described together with their implications for the understanding of the site. Additional investigations are identified that could further reduce risks and uncertainties, and enable progress toward a full storage permit application. Permit performance conditions are presented as SiteChar-recommended useful tools for discussion between the competent authority and operator

Classifying and Predicting Surgical Complications After Laryngectomy: A Novel Approach to Diagnosing and Treating Patients

Objectives: The total laryngectomy is one of the most standardized major surgical procedures in otolaryngology. Several studies have proposed the Clavien-Dindo classification (CDC) as a solution to classifying postoperative complications into 5 grades from less severe to severe. Yet more data on classifying larger patient populations undergoing major otolaryngologic surgery according to the CDC are needed. Predicting postoperative complications in clinical practice is often subject to generalized clinical scoring systems with uncertain predictive abilities for otolaryngologic surgery. Machine learning offers methods to predict postoperative complications based on data obtained prior to surgery. Methods: We included all patients (N = 148) who underwent a total laryngectomy after diagnosis of squamous cell carcinoma at our institution. A univariate and multivariate logistic regression analysis of multiple complex risk factors was performed, and patients were grouped into severe postoperative complications (CDC >= 4) and less severe complications. Four different commonly used machine learning algorithms were trained on the dataset. The best model was selected to predict postoperative complications on the complete dataset. Results: Univariate analysis showed that the most significant predictors for postoperative complications were the Charlson Comorbidity Index (CCI) and whether reconstruction was performed intraoperatively. A multivariate analysis showed that the CCI and reconstruction remained significant. The commonly used AdaBoost algorithm achieved the highest area under the curve with 0.77 with high positive and negative predictive values in subsequent analysis. Conclusions: This study shows that postoperative complications can be classified according to the CDC with the CCI being a useful screening tool to predict patients at risk for postoperative complications. We provide evidence that could help identify single patients at risk for complications and customize treatment accordingly which could finally lead to a custom approach for every patient. We also suggest that there is no increase in complications with patients of higher age

Bone Marrow-Specific Knock-In of a Non-Activatable Ikkα Kinase Mutant Influences Haematopoiesis but Not Atherosclerosis in Apoe-Deficient Mice

Background: The Ikkα kinase, a subunit of the NF-kappa B-activating IKK complex, has emerged as an important regulator of inflammatory gene expression. However, the role of Ikkα-mediated phosphorylation in haematopoiesis and atherogenesis remains unexplored. In this study, we investigated the effect of a bone marrow (BM)-specific activation-resistant Ikk alpha mutant knock-in on haematopoiesis and atherosclerosis in mice. Methods and Results: Apolipoprotein E (Apoe)-deficient mice were transplanted with BM carrying an activation-resistant Ikkα gene (Ikkα(AA/AA) Apoe(-/-)) or with Ikkα(+/+) Apoe(-/-) BM as control and were fed a high-cholesterol diet for 8 or 13 weeks. Interestingly, haematopoietic profiling by flow cytometry revealed a significant decrease in B-cells, regulatory T-cells and effector memory T-cells in Ikkα(AA/AA) Apoe(-/-) BM-chimeras, whereas the naive T-cell population was increased. Surprisingly, no differences were observed in the size, stage or cellular composition of atherosclerotic lesions in the aorta and aortic root of Ikkα(AA/AA) Apoe(-/-) vs Ikkα(+/+) Apoe(-/-) BM-transplanted mice, as shown by histological and immunofluorescent stainings. Necrotic core sizes, apoptosis, and intracellular lipid deposits in aortic root lesions were unaltered. In vitro, BM-derived macrophages from Ikkα(AA/AA) Apoe(-/-) vs Ikkα(+/+) Apoe(-/-) mice did not show significant differences in the uptake of oxidized low-density lipoproteins (oxLDL), and, with the exception of Il-12, the secretion of inflammatory proteins in conditions of Tnf-α or oxLDL stimulation was not significantly altered. Furthermore, serum levels of inflammatory proteins as measured with a cytokine bead array were comparable. Conclusion: Our data reveal an important and previously unrecognized role of haematopoietic Ikkα kinase activation in the homeostasis of B-cells and regulatory T-cells. However, transplantation of Ikkα AA mutant BM did not affect atherosclerosis in Apoe(-/-) mice. This suggests that the diverse functions of Ikkα in haematopoietic cells may counterbalance each other or may not be strong enough to influence atherogenesis, and reveals that targeting haematopoietic Ikkα kinase activity alone does not represent a therapeutic approach

Multi-omics analysis of innate and adaptive responses to BCG vaccination reveals epigenetic cell states that predict trained immunity

<p>This repository contains personal immune profiles of 323 healthy individuals (300BCG) subjected to Bacillus Calmette-Guérin (BCG) with blood samples collected immediately before (day 0), and 14 and 90 days after the vaccination. The personal immune profiles comprise:</p> <ul> <li>immune cell concentrations measured with flow cytometry and a hematology analyzer</li> <li>plasma concentrations of 73 circulating inflammatory markers</li> <li>30 measurements of cytokine and lactate production capacity of peripheral blood mononuclear cells (PBMCs) in response to four microbial stimuli (Candida albicans, Escherichia coli lipopolysaccharide [LPS], Staphylococcus aureus, Mycobacterium tuberculosis).</li> </ul> <p>Visit <a href="http://300BCG.bocklab.org/">http://300BCG.bocklab.org/</a> to learn more.</p&gt

Leukocyte numbers and frequencies of leukocyte subsets in <i>Apoe^−/−</i> mice transplanted with <i>Ikkα^AA/AAApoe^−/−</i> or <i>Ikkα^+/+Apoe^−/−</i> BM.

<p>Peripheral blood leukocyte counts were determined after 8 weeks of high-fat diet (n = 8). Leukocyte subset frequencies were quantified by flow cytometry after 13 weeks of high-fat diet (n = 18–19).</p

Knock-in of <i>Ikkα^AA/AA</i> in haematopoietic cells does not influence apoptosis in atherosclerotic lesions.

<p>Analysis of aortic root lesions of <i>Apoe^−/−</i> mice transplanted with <i>Ikkα^AA/AAApoe^−/−</i> or <i>Ikkα^+/+Apoe^−/−</i> BM and receiving a high-fat diet for 13 weeks. (<b>A</b>) Quantification of necrotic cores as percentage of plaque area. (B–C) Quantification of apoptotic cells (Tunel⁺, B) and apoptotic macrophages (Tunel⁺Mac2⁺, C) as percentage of all plaque cells. Graphs represent the mean ± SEM (n = 10–12).</p

<i>Ikkα^AA/AAApoe^−/−</i> BM-chimeras have less B-cells, T_reg and effector memory T-cells, and more naive T-cells.

<p>Shown is flow cytometric analysis of peripheral blood, thymus and secondary lymphoid organs of <i>Apoe^−/−</i> mice transplanted with <i>Ikkα^AA/AAApoe^−/−</i> or <i>Ikkα^+/+Apoe^−/−</i> BM and receiving a high-cholesterol diet for 13 weeks. (<b>A</b>) Cd19⁺ B-cell and Cd3⁺ T-cell populations as percentage of Cd45⁺ leukocytes, and Cd4⁺ and Cd8a⁺ T-cell subsets as percentage of Cd3⁺ T-cells in peripheral blood. (<b>B</b>) Cd3⁺Cd4⁺Cd25⁺Foxp3⁺ regulatory T-cell (T_reg) levels as percentage of Cd3⁺ T-cells and Cd45⁺ leukocytes. (<b>C</b>) Cd3⁺Cd44^lowCd62L^high naive T-cells and Cd3⁺Cd44^highCd62L^low effector memory T-cells as percentage of Cd3⁺ T-cells and Cd45⁺ leukocytes. Left Y-axes belong to naive T-cells, right Y-axes to effector memory T-cells. (<b>D</b>) Cd11c⁺MhcII⁺ conventional dendritic cells (cDCs) and Cd11c⁺Cd11b⁻440c⁺ plasmacytoid DCs (pDCs) as percentage of Cd45⁺ leukocytes <i>(left)</i>. Surface expression of MhcII on splenic cDCs and pDCs <i>(right)</i>. (<b>A–D</b>) All graphs represent the mean ± SEM (n = 18–19); 2-tailed t-test, *P<0.05, **P<0.01, ***P<0.001.</p