@article{NentwichRufGirschicketal.2019, author = {Nentwich, Julia and Ruf, Katharina and Girschick, Hermann and Holl-Wieden, Annette and Morbach, Henner and Hebestreit, Helge and Hofmann, Christine}, title = {Physical activity and health-related quality of life in chronic non-bacterial osteomyelitis}, series = {Pediatric Rheumatology}, volume = {17}, journal = {Pediatric Rheumatology}, doi = {10.1186/s12969-019-0351-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323710}, year = {2019}, abstract = {Background Chronic non-bacterial osteomyelitis (CNO) is an autoinflammatory disorder of the skeletal system of yet unknown etiology. Patients present with local bone pain and inflammation and - to our experience - often suffer from functional impairment with significant disabilities of daily life. The objective of this study was to assess physical activity, fitness and health-related quality of life (HRQOL) in adolescents with established diagnosis of CNO versus healthy controls (HC). Methods 15 patients with CNO and 15 age and gender matched HC aged 13-18 years, completed questionnaires, performed an incremental exercise test with gas exchange measures up to voluntary fatigue and wore an accelerometer over 7 days at home to assess physical activity behavior. Results At the time of assessment, 5 CNO patients were in clinical, one in radiological and 5 in clinical and radiological remission. 7 did not receive any therapy at the time of assessment. The results of the exercise test and of the accelerometry did not show any significant difference between CNO and HC. However, reported sports participation was lower in patients with CNO and PedsQL3.0 and 4.0 showed significant lower values in most of the scores indicating reduced HRQOL. Conclusion Although most CNO patients showed a favorable course of disease without any relevant differences in objective measurements of physical activity and fitness versus HC at the time of assessment, questionnaires revealed perceived limitations. Further studies are needed to measure HRQOL and to validate questionnaires in patients with CNO against objective measures including more participants with a higher level of disease activity.}, language = {en} } @article{KlenkeQuastPrelogetal.2018, author = {Klenke, Daniela and Quast, Anja and Prelog, Martina and Holl-Wieden, Annette and Riekert, Maximilian and Stellzig-Eisenhauer, Angelika and Meyer-Marcotty, Philipp}, title = {TMJ pathomorphology in patients with JIA-radiographic parameters for early diagnosis-}, series = {Head \& Face Medicine}, volume = {14}, journal = {Head \& Face Medicine}, doi = {10.1186/s13005-018-0173-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325882}, year = {2018}, abstract = {Background Juvenile idiopathic arthritis (JIA) is often accompanied by pathomorphological changes to the temporomandibular joint (TMJ). By analyzing orthodontical orthopantomograms of JIA patients the aims of the study were a) classification of condyle changes, b) quantification of bony asymmetries of condylar destruction and c) detection of relationships between disease duration and TMJ-involvement. Patients/Methods 46 caucasian JIA-patients (28 female; 18 male; < 16.0 years) were enrolled, each joint (n = 92) was morphologically assessed by means of orthopantomogram, quantitatively analysed and compared with duration of general disease. Condyle morphology was assessed using the Billiau scale for severity of destruction [1]. The quantitative analysis was based on ratios of condyle, ramus and mandible height. Results Patients were divided into groups (Group I - slightly affected, n = 36; Billiau severity 0-2; condyle findings: X-ray normal, condyle erosions, condylar flattening; Group II - severely affected, N = 10; Billiau severity 3-4; condyle findings: condylar flattenings and erosions, unilateral/bilateral complete loss of condyles), based on morphological analysis of condylar destruction. Duration of disease was significantly longer in Group II (8.9 ± 5.2 years) than in Group I (4.6 ± 4.7 years). Asymmetries of condyle, ramus and mandible height, quantitatively analysed by contralateral comparison, were significantly more marked in patients of Group II than of Group I. Conclusions Orthopantomogram imaging can be used in orthodontics clinical routine to detect TMJ-pathologies and is an important reference for monitoring progression of JIA. Classification into severe and slightly affected TMJ is possible by analysis of condylar pathomorphology. An association between degree of destruction, extent of lower jaw asymmetry and disease duration is suggested by the results.}, language = {en} } @article{HetzerOrthHoellerWuerzneretal.2019, author = {Hetzer, Benjamin and Orth-H{\"o}ller, Dorothea and W{\"u}rzner, Reinhard and Kreidl, Peter and Lackner, Michaela and M{\"u}ller, Thomas and Knabl, Ludwig and Geisler-Moroder, Daniel Rudolf and Mellmann, Alexander and Sesli, {\"O}zcan and Holzknecht, Jeanett and Noce, Damia and Akarathum, Noppadon and Chotinaruemol, Somporn and Prelog, Martina and Oberdorfer, Peninnah}, title = {"Enhanced acquisition of antibiotic-resistant intestinal E. coli during the first year of life assessed in a prospective cohort study"}, series = {Antimicrobial Resistance \& Infection Control}, volume = {8}, journal = {Antimicrobial Resistance \& Infection Control}, doi = {10.1186/s13756-019-0522-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320284}, year = {2019}, abstract = {Background Increasing bacterial resistance to antibiotics is a serious problem worldwide. We sought to record the acquisition of antibiotic-resistant Escherichia coli (E. coli) in healthy infants in Northern Thailand and investigated potential determinants. Methods Stool samples from 142 infants after birth, at ages 2wk, 2mo, 4 to 6mo, and 1y, and parent stool samples were screened for E. coli resistance to tetracycline, ampicillin, co-trimoxazole, and cefazoline by culture, and isolates were further investigated for multiresistance by disc diffusion method. Pulsed-field gel electrophoresis was performed to identify persistent and transmitted strains. Genetic comparison of resistant and transmitted strains was done by multilocus sequence typing (MLST) and strains were further investigated for extra- and intra-intestinal virulence factors by multiplex PCR. Results Forty-seven (33\%) neonatal meconium samples contained resistant E. coli. Prevalence increased continuously: After 1y, resistance proportion (tetracycline 80\%, ampicillin 72\%, co-trimoxazole 66\%, cefazoline 35\%) almost matched those in parents. In 8 infants (6\%), identical E. coli strains were found in at least 3 sampling time points (suggesting persistence). Transmission of resistant E. coli from parents to child was observed in only 8 families. MLST showed high diversity. We could not identify any virulence genes or factors associated with persistence, or transmission of resistant E. coli. Full-term, vaginal birth and birth in rural hospital were identified as risk factors for early childhood colonization with resistant E. coli. Conclusion One third of healthy Thai neonates harboured antibiotic-resistant E. coli in meconium. The proportion of resistant E. coli increased during the first year of life almost reaching the value in adults. We hypothesize that enhancement of infection control measures and cautious use of antibiotics may help to control further increase of resistance.}, language = {en} } @article{LiangBencurovaPsotaetal.2021, author = {Liang, Chunguang and Bencurova, Elena and Psota, Eric and Neurgaonkar, Priya and Prelog, Martina and Scheller, Carsten and Dandekar, Thomas}, title = {Population-predicted MHC class II epitope presentation of SARS-CoV-2 structural proteins correlates to the case fatality rates of COVID-19 in different countries}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {5}, issn = {1422-0067}, doi = {10.3390/ijms22052630}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258936}, year = {2021}, abstract = {We observed substantial differences in predicted Major Histocompatibility Complex II (MHCII) epitope presentation of SARS-CoV-2 proteins for different populations but only minor differences in predicted MHCI epitope presentation. A comparison of this predicted epitope MHC-coverage revealed for the early phase of infection spread (till day 15 after reaching 128 observed infection cases) highly significant negative correlations with the case fatality rate. Specifically, this was observed in different populations for MHC class II presentation of the viral spike protein (p-value: 0.0733 for linear regression), the envelope protein (p-value: 0.023), and the membrane protein (p-value: 0.00053), indicating that the high case fatality rates of COVID-19 observed in some countries seem to be related with poor MHC class II presentation and hence weak adaptive immune response against these viral envelope proteins. Our results highlight the general importance of the SARS-CoV-2 structural proteins in immunological control in early infection spread looking at a global census in various countries and taking case fatality rate into account. Other factors such as health system and control measures become more important after the early spread. Our study should encourage further studies on MHCII alleles as potential risk factors in COVID-19 including assessment of local populations and specific allele distributions.}, language = {en} } @phdthesis{Roberts2023, author = {Roberts, Stephanie Kimberly}, title = {Impfausbildung und Selbsteinsch{\"a}tzung des Impfwissens von Medizinstudierenden in Bayern im Sommer- und Wintersemester 2018}, doi = {10.25972/OPUS-28246}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282465}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Impfungen sind essenziell zur Pr{\"a}vention vieler Erkrankungen. F{\"u}r die Impfentscheidung von Patienten spielt die {\"a}rztliche Beratung eine wichtige Rolle. Die universit{\"a}re Lehre sollte das notwendige Wissen zu Impfungen vermitteln. Die vorliegende Studie untersuchte die Selbsteinsch{\"a}tzung des Impfwissens von Medizinstudierenden sowie die Struktur der Impfausbildung im Medizinstudium. In einer Umfrage wurden Medizinstudierende an den damaligen f{\"u}nf medizinischen Fakult{\"a}ten in Bayern im Sommer- und Wintersemester 2018 zu ihrem Impfwissen und ihrer Impfausbildung befragt.}, subject = {Impfung}, language = {de} } @article{HagemannNeuhausDahlmannetal.2019, author = {Hagemann, Carsten and Neuhaus, Nikolas and Dahlmann, Mathias and Kessler, Almuth F. and Kobelt, Dennis and Herrmann, Pia and Eyrich, Matthias and Freitag, Benjamin and Linsenmann, Thomas and Monoranu, Camelia M. and Ernestus, Ralf-Ingo and L{\"o}hr, Mario and Stein, Ulrike}, title = {Circulating MACC1 transcripts in glioblastoma patients predict prognosis and treatment response}, series = {Cancers}, volume = {11}, journal = {Cancers}, number = {6}, issn = {2072-6694}, doi = {10.3390/cancers11060825}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-197327}, year = {2019}, abstract = {Glioblastoma multiforme is the most aggressive primary brain tumor of adults, but lacksreliable and liquid biomarkers. We evaluated circulating plasma transcripts of metastasis-associatedin colon cancer-1 (MACC1), a prognostic biomarker for solid cancer entities, for prediction of clinicaloutcome and therapy response in glioblastomas. MACC1 transcripts were significantly higher inpatients compared to controls. Low MACC1 levels clustered together with other prognosticallyfavorable markers. It was associated with patients' prognosis in conjunction with the isocitratedehydrogenase (IDH) mutation status: IDH1 R132H mutation and low MACC1 was most favorable(median overall survival (OS) not yet reached), IDH1 wildtype and high MACC1 was worst (medianOS 8.1 months), while IDH1 wildtype and low MACC1 was intermediate (median OS 9.1 months).No patients displayed IDH1 R132H mutation and high MACC1. Patients with low MACC1 levelsreceiving standard therapy survived longer (median OS 22.6 months) than patients with high MACC1levels (median OS 8.1 months). Patients not receiving the standard regimen showed the worstprognosis, independent of MACC1 levels (low: 6.8 months, high: 4.4 months). Addition of circulatingMACC1 transcript levels to the existing prognostic workup may improve the accuracy of outcomeprediction and help define more precise risk categories of glioblastoma patients.}, language = {en} } @article{RufBadranSiauwetal.2021, author = {Ruf, Katharina and Badran, Alaa and Siauw, C{\´e}line and Haubitz, Imme and Schlegel, Paul-Gerhardt and Hebestreit, Helge and H{\"a}rtel, Christoph and Wiegering, Verena}, title = {Does allogeneic stem cell transplantation in survivors of pediatric leukemia impact regular physical activity, pulmonary function, and exercise capacity?}, series = {Molecular and Cellular Pediatrics}, volume = {8}, journal = {Molecular and Cellular Pediatrics}, doi = {10.1186/s40348-021-00127-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265528}, year = {2021}, abstract = {Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved survival in high-risk childhood leukemia but is associated with long-term sequelae such as impaired pulmonary function and reduced exercise capacity impacting quality of life. Methods A convenience sample of 17 patients after allo-HSCT (HSCT—12 male, age 15.7±6.7 years, time after HSCT 5.3±2.8 years) underwent pulmonary function testing, echocardiography, and an incremental exercise test on a bike. Physical activity and health-related quality of life were assessed by questionnaires (7-day physical activity recall, PEDS-QL). Seventeen healthy age- and gender-matched controls served as control group (CG) for results of pulmonary function and exercise testing. Results HSCT showed reduced pulmonary function (HSCT vs. CG: FEV1 90.5±14.0 vs. 108.0±8.7\%pred; FVC 88.4±19.3 vs. 107.6±6.9\%pred, DLCO 75.3±23.6 vs. 104.9±12.8\%pred) and exercise capacity (VO2peak 89±30.8\%pred, CG 98±17.5\%pred; Wmax 84±21.7\%pred, CG 115±22.8\%pred), but no relevant cardiac dysfunction and a good quality of life (PEDS-QL mean overall score 83.3±10.7). Differences in peak oxygen uptake between groups were mostly explained by 5 adolescent patients who underwent total body irradiation for conditioning. They showed significantly reduced diffusion capacity and reduced peak oxygen uptake. Patients reported a mean time of inactivity of 777±159min/day, moderate activity of 110±107 min/day, hard activity of 35±36 min/day, and very hard activity of 23±22 min/day. A higher amount of inactivity was associated with a lower peak oxygen uptake (correlation coefficient tau -0.48, p=0.023). Conclusions This pilot study shows that although patients after allo-HSCT reported a good quality of life, regular physical activity and exercise capacity are reduced in survivors of stem cell transplantation, especially in adolescents who are treated with total body irradiation for conditioning. Factors hindering regular physical activity need to be identified and exercise counseling should be part of follow-up visits in these patients.}, language = {en} } @article{LorenzKressZaumetal.2021, author = {Lorenz, Delia and Kress, Wolfram and Zaum, Ann-Kathrin and Speer, Christian P. and Hebestreit, Helge}, title = {Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency}, series = {BMC Pediatrics}, volume = {21}, journal = {BMC Pediatrics}, doi = {10.1186/s12887-021-02767-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261084}, year = {2021}, abstract = {Background The spondylodysplastic Ehlers-Danlos subtype (OMIM \#130070) is a rare connective tissue disorder characterized by a combination of connective tissue symptoms, skeletal features and short stature. It is caused by variants in genes encoding for enzymes involved in the proteoglycan biosynthesis or for a zinc transporter. Presentation of cases We report two brothers with a similar phenotype of short stature, joint hypermobility, distinct craniofacial features, developmental delay and severe hypermetropia indicative for a spondylodysplastic Ehlers-Danlos subtype. One also suffered from a recurrent pneumothorax. Gene panel analysis identified two compound heterozygous variants in the B4GALT7 gene: c.641G > A and c.723 + 4A > G. B4GALT7 encodes for galactosyltransferase I, which is required for the initiation of glycosaminoglycan side chain synthesis of proteoglycans. Conclusions This is a first full report on two cases with spondylodysplastic Ehlers-Danlos syndrome and the c.723 + 4A > G variant of B4GALT7. The recurrent pneumothoraces observed in one case expand the variable phenotype of the syndrome.}, language = {en} } @article{RufWirbelauerBeissertetal.2018, author = {Ruf, Katharina and Wirbelauer, Johannes and Beissert, Antje and Frieauff, Eric}, title = {Successful treatment of severe arterial hypotension and anuria in a preterm infant with renal tubular dysgenesis- a case report}, series = {Maternal Health, Neonatology and Perinatology}, volume = {4}, journal = {Maternal Health, Neonatology and Perinatology}, number = {27}, doi = {10.1186/s40748-018-0095-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177405}, year = {2018}, abstract = {Background: Oligohydramnios sequence can be caused by renal tubular dysgenesis (RTD), a rare condition resulting in pulmonary and renal morbidity. Besides typical features of Potter-sequence, the infants present with severe arterial hypotension and anuria as main symptoms. Establishing an adequate arterial blood pressure and sufficient renal perfusion is crucial for the survival of these infants. Case presentation: We describe a male preterm infant of 34 + 0 weeks of gestation. Prenatally oligohydramnios of unknown cause was detected. After uneventful delivery and good adaptation the infant developed respiratory distress due to a spontaneous right-sided pneumothorax and required thoracocentesis and placement of a chest tube; he showed no major respiratory concerns thereafter and needed only minimal ventilatory support. Echocardiography revealed no abnormalities, especially no pulmonary hypertension. However, he suffered from severe arterial hypotension and anuria refractory to catecholamine therapy (dobutamine, epinephrine and noradrenaline). After 36 h of life, vasopressin therapy was initiated resulting in an almost immediate stabilization of arterial blood pressure and subsequent onset of diuresis. Therapy with vasopressin was necessary for three weeks to maintain adequate arterial blood pressure levels and diuresis. Sepsis and adrenal insufficiency were ruled out as inflammation markers, microbiological tests and cortisol level were normal. At two weeks of age, our patient developed electrolyte disturbances which were successfully treated with fludrocortisone. He did not need renal replacement therapy. Genetic analyses revealed a novel compound hyterozygous mutation of RTD. Now 17 months of age, the patient is in clinically stable condition with treatment of fludrocortisone and sodium bicarbonate. He suffers from stage 2 chronic kidney disease; blood pressure, motor and cognitive development are normal. Conclusions: RTD is a rare cause of oligohydramnios sequence. Next to pulmonary hypoplasia, severe arterial hypotension is responsible for poor survival. We present the only second surviving infant with RTD, who did not require renal replacement therapy during the neonatal period. It can be speculated whether the use of vasopressin prevents renal replacement therapy as vasopressin increases urinary output by improving renal blood flow.}, language = {en} } @article{GirschickWolfMorbachetal.2015, author = {Girschick, Hermann and Wolf, Christine and Morbach, Henner and Hertzberg, Christoph and Lee-Kirsch, Min Ae}, title = {Severe immune dysregulation with neurological impairment and minor bone changes in a child with spondyloenchondrodysplasia due to two novel mutations in the ACP5 gene}, series = {Pediatric Rheumatology}, volume = {13}, journal = {Pediatric Rheumatology}, number = {37}, doi = {10.1186/s12969-015-0035-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-149990}, year = {2015}, abstract = {Spondyloenchondrodysplasia (SPENCD) is a rare skeletal dysplasia, characterized by metaphyseal lesions, neurological impairment and immune dysregulation associated with lupus-like features. SPENCD is caused by biallelic mutations in the ACP5 gene encoding tartrate-resistant phosphatase. We report on a child, who presented with spasticity, multisystem inflammation, autoimmunity and immunodeficiency with minimal metaphyseal changes due to compound heterozygosity for two novel ACP5 mutations. These findings extend the phenotypic spectrum of SPENCD and indicate that ACP5 mutations can cause severe immune dysregulation and neurological impairment even in the absence of metaphyseal dysplasia.}, language = {en} } @article{GoettlerNieklerLieseetal.2022, author = {Goettler, David and Niekler, Patricia and Liese, Johannes G. and Streng, Andrea}, title = {Epidemiology and direct healthcare costs of Influenza-associated hospitalizations - nationwide inpatient data (Germany 2010-2019)}, series = {BMC Public Health}, volume = {22}, journal = {BMC Public Health}, doi = {10.1186/s12889-022-12505-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265888}, year = {2022}, abstract = {Introduction Detailed and up-to-date data on the epidemiology and healthcare costs of Influenza are fundamental for public health decision-making. We analyzed inpatient data on Influenza-associated hospitalizations (IAH), selected complications and risk factors, and their related direct costs for Germany during ten consecutive years. Methods We conducted a retrospective cost-of-illness study on patients with laboratory-confirmed IAH (ICD-10-GM code J09/J10 as primary diagnosis) by ICD-10-GM-based remote data query using the Hospital Statistics database of the German Federal Statistical Office. Clinical data and associated direct costs of hospital treatment are presented stratified by demographic and clinical variables. Results Between January 2010 to December 2019, 156,097 persons were hospitalized due to laboratory-confirmed Influenza (J09/J10 primary diagnosis). The annual cumulative incidence was low in 2010, 2012 and 2014 (1.3 to 3.1 hospitalizations per 100,000 persons) and high in 2013 and 2015-2019 (12.6 to 60.3). Overall direct per patient hospitalization costs were mean (SD) 3521 EUR (± 8896) and median (IQR) 1805 EUR (1502; 2694), with the highest mean costs in 2010 (mean 8965 EUR ± 26,538) and the lowest costs in 2012 (mean 2588 EUR ± 6153). Mean costs were highest in 60-69 year olds, and in 50-59, 70-79 and 40-49 year olds; they were lowest in 10-19 year olds. Increased costs were associated with conditions such as diabetes (frequency 15.0\%; 3.45-fold increase compared to those without diabetes), adiposity (3.3\%; 2.09-fold increase) or immune disorders (5.6\%; 1.88-fold increase) and with Influenza-associated complications such as Influenza pneumonia (24.3\%; 1.95-fold), bacterial pneumonia (6.3\%; 3.86-fold), ARDS (1.2\%; 10.90-fold increase) or sepsis (2.3\%; 8.30-fold). Estimated overall costs reported for the 10-year period were 549.6 Million euros (95\% CI 542.7-556.4 million euros). Conclusion We found that the economic burden of IAH in Germany is substantial, even when considering solely laboratory-confirmed IAH reported as primary diagnosis. The highest costs were found in the elderly, patients with certain underlying risk factors and patients who required advanced life support treatment, and median and mean costs showed considerable variations between single years. Furthermore, there was a relevant burden of disease in middle-aged adults, who are not covered by the current vaccination recommendations in Germany.}, language = {en} } @article{WiegeringRiedmeierThompsonetal.2022, author = {Wiegering, Verena and Riedmeier, Maria and Thompson, Lester D. R. and Virgone, Calogero and Redlich, Antje and Kuhlen, Michaela and Gultekin, Melis and Yalcin, Bilgehan and Decarolis, Boris and H{\"a}rtel, Christoph and Schlegel, Paul-Gerhardt and Fassnacht, Martin and Timmermann, Beate}, title = {Radiotherapy for pediatric adrenocortical carcinoma - Review of the literature}, series = {Clinical and Translational Radiation Oncology}, volume = {35}, journal = {Clinical and Translational Radiation Oncology}, doi = {10.1016/j.ctro.2022.05.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300472}, pages = {56-63}, year = {2022}, abstract = {Background and purpose Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting. Materials and methods We searched the PubMed and Embase database for manuscripts regarding RT for pACC. Results We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70\% female); 78\% of patients presented with hormonal activity. RT was mostly performed for curative intent (78\%). 88\% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76\%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64\% of the patients died of disease, with 33\% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33\%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient. Conclusions Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy.}, language = {en} } @article{FischerKnopDanhofetal.2022, author = {Fischer, Julia and Knop, Stefan and Danhof, Sophia and Einsele, Hermann and Keller, Daniela and L{\"o}ffler, Claudia}, title = {The influence of baseline characteristics, treatment and depression on health-related quality of life in patients with multiple myeloma: a prospective observational study}, series = {BMC Cancer}, volume = {22}, journal = {BMC Cancer}, doi = {10.1186/s12885-022-10101-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300435}, year = {2022}, abstract = {Background Multiple myeloma (MM) is the third most common hematologic malignancy with increasing importance due to improving treatment strategies and long-term outcomes in an aging population. This study aims to analyse influencing factors on health-related quality of life (HRQoL), such as treatment strategies, participation in a clinical trial and patient characteristics like anxiety, depression, gender, and age. A better understanding of the individual factors in context with HRQoL could provide a helpful instrument for clinical decisions. Methods In this prospective observational study, the HRQoL of MM patients with different therapies (first-line and relapse) was quantified by standardized questionnaires (EORTC QLQ-C30 and -MY20) in the context of sociodemographic data, individual anxiety and depressiveness (PHQ-4), and a selected number of clinical parameters and symptoms at defined time-points before, during, and after therapy. Results In total, 70 patients were included in the study. The median age of the study cohort was 62 years. 44\% were female and 56\% were male patients. More than half of the patients were fully active with an ECOG 0. Global health status was significantly higher in patients with first-line treatment and even increased after start of therapy, while the pain level decreased. In contrast, patients with relapsed MM reported a decreasing global health status and increasing pain. Additionally, there was a higher global health status in less anxious/depressive patients. HRQoL decreased significantly after start of chemotherapy in the parameters body image, side effects of treatment, and cognitive functioning. Tandem stem-cell transplantation was not found to be a risk factor for higher impairment of HRQoL. Participation in a clinical study led to an improvement of most aspects of HRQoL. Among others, increased anxiety and depression, female gender, older age, impaired performance status, and recurrent disease can be early indicators for a reduced HRQoL. Conclusion This study showed the importance of regular longitudinal assessments of patient reported outcomes (PROs) in routine clinical care. For the first time, to our knowledge, we were able to demonstrate a potential impact between participation in clinical trials and HRQoL. However, due to frequently restrictive inclusion criteria for clinical trials, these MM patients might not be directly comparable with patients treated within standard therapy concepts. Further studies are needed to clarify the relevance of this preliminary data in order to develop an individualized, patient-centred, therapy concept.}, language = {en} } @article{SauerLiHollWiedenetal.2017, author = {Sauer, Alexander and Li, Mengxia and Holl-Wieden, Annette and Pabst, Thomas and Neubauer, Henning}, title = {Readout-segmented multi-shot diffusion-weighted MRI of the knee joint in patients with juvenile idiopathic arthritis}, series = {Pediatric Rheumatology}, volume = {15}, journal = {Pediatric Rheumatology}, number = {73}, doi = {10.1186/s12969-017-0203-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158095}, year = {2017}, abstract = {Background: Diffusion-weighted MRI has been proposed as a new technique for imaging synovitis without intravenous contrast application. We investigated diagnostic utility of multi-shot readout-segmented diffusion-weighted MRI (multi-shot DWI) for synovial imaging of the knee joint in patients with juvenile idiopathic arthritis (JIA). Methods: Thirty-two consecutive patients with confirmed or suspected JIA (21 girls, median age 13 years) underwent routine 1.5 T MRI with contrast-enhanced T1w imaging (contrast-enhanced MRI) and with multi-shot DWI (RESOLVE, b-values 0-50 and 800 s/mm\(^2\)). Contrast-enhanced MRI, representing the diagnostic standard, and diffusion-weighted images at b = 800 s/mm\(^2\) were separately rated by three independent blinded readers at different levels of expertise for the presence and the degree of synovitis on a modified 5-item Likert scale along with the level of subjective diagnostic confidence. Results: Fourteen (44\%) patients had active synovitis and joint effusion, nine (28\%) patients showed mild synovial enhancement not qualifying for arthritis and another nine (28\%) patients had no synovial signal alterations on contrast-enhanced imaging. Ratings by the 1st reader on contrast-enhanced MRI and on DWI showed substantial agreement (κ = 0.74). Inter-observer-agreement was high for diagnosing, or ruling out, active arthritis of the knee joint on contrast-enhanced MRI and on DWI, showing full agreement between 1st and 2nd reader and disagreement in one case (3\%) between 1st and 3rd reader. In contrast, ratings in cases of absent vs. little synovial inflammation were markedly inconsistent on DWI. Diagnostic confidence was lower on DWI, compared to contrast-enhanced imaging. Conclusion: Multi-shot DWI of the knee joint is feasible in routine imaging and reliably diagnoses, or rules out, active arthritis of the knee joint in paediatric patients without the need of gadolinium-based i.v. contrast injection. Possibly due to "T2w shine-through" artifacts, DWI does not reliably differentiate non-inflamed joints from knee joints with mild synovial irritation.}, language = {en} } @article{FaustFreitagBarrientosetal.2021, author = {Faust, Kirstin and Freitag, Nancy and Barrientos, Gabriela and Hartel, Christoph and Blois, Sandra M.}, title = {Galectin-Levels Are Elevated in Infants Born Preterm Due to Amniotic Infection and Rapidly Decline in the Neonatal Period}, series = {Frontiers in Immunology}, volume = {11}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2020.599104}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230701}, year = {2021}, abstract = {Galectin (gal)-1, -3, and -9 are members of a family of glycan binding proteins that mediate complex interactions between decidual, inflammatory and trophoblast cells modulating several processes during gestation, control of the maternal immune system, and parturition. Their immunomodulatory role in preterm birth and postnatal expression in preterm infants is unknown. We performed a single center prospective study of 170 preterm infants with a gestational age below 35 weeks. Peripheral venous blood samples were collected during the neonatal period and galectin-1, -3, and -9 were determined by ELISA. We noted a strong decline of circulating gal-1 and -3 levels but not gal-9 from birth to day 7 of life. There was an inverse correlation of gal-1 and -3 levels at birth with gestational age. Gal-1 levels were remarkably increased in infants born to amniotic infection syndrome (AIS), which was also observed for gal-9 levels. Infants who developed early-onset sepsis had higher levels of gal-3 at day 1 as compared to unaffected infants. Our observational data imply that galectin-1, -3, and -9 levels are elevated in preterm infants born in an inflammatory milieu such as AIS or EOS. Future studies need to address whether galectins mediate inflammation-induced preterm birth and could therefore be a target for clinical trials.}, language = {en} } @article{GlaserSilwedelFehrholzetal.2017, author = {Glaser, Kirsten and Silwedel, Christine and Fehrholz, Markus and Waaga-Gasser, Ana M. and Henrich, Birgit and Claus, Heike and Speer, Christian P.}, title = {Ureaplasma Species Differentially Modulate Pro- and Anti-Inflammatory Cytokine Responses in Newborn and Adult Human Monocytes Pushing the State Toward Pro-Inflammation}, series = {Frontiers in Cellular and Infection Microbiology}, volume = {7}, journal = {Frontiers in Cellular and Infection Microbiology}, number = {484}, doi = {10.3389/fcimb.2017.00484}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-169958}, year = {2017}, abstract = {Background: Ureaplasma species have been associated with chorioamnionitis and preterm birth and have been implicated in the pathogenesis of neonatal short and long-term morbidity. However, being mostly commensal bacteria, controversy remains on the pro-inflammatory capacity of Ureaplasma. Discussions are ongoing on the incidence and impact of prenatal, perinatal, and postnatal infection. The present study addressed the impact of Ureaplasma isolates on monocyte-driven inflammation. Methods: Cord blood monocytes of term neonates and adult monocytes, either native or LPS-primed, were cultured with Ureaplasma urealyticum (U. urealyticum) serovar 8 (Uu8) and Ureaplasma parvum serovar 3 (Up3). Using qRT-PCR, cytokine flow cytometry, and multi-analyte immunoassay, we assessed mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, IL-12p40, IL-10, and IL-1 receptor antagonist (IL-1ra) as well as Toll-like receptor (TLR) 2 and TLR4. Results: Uu8 and Up3 induced mRNA expression and protein release of TNF-α, IL-1β and IL-8 in term neonatal and adult monocytes (p < 0.01 and p < 0.05). Intracellular protein expression of TNF-α, IL-1β and IL-8 in Ureaplasma-stimulated cells paralleled those results. Ureaplasma-induced cytokine levels did not significantly differ from LPS-mediated levels except for lower intracellular IL-1β in adult monocytes (Uu8: p < 0.05). Remarkably, ureaplasmas did not induce IL-12p40 response and promoted lower amounts of anti-inflammatory IL-10 and IL-1ra than LPS, provoking a cytokine imbalance more in favor of pro-inflammation (IL-1β/IL-10, IL-8/IL-10 and IL-8/IL-1ra: p < 0.01, vs. LPS). In contrast to LPS, both isolates induced TLR2 mRNA in neonatal and adult cells (p < 0.001 and p < 0.05) and suppressed TLR4 mRNA in adult monocytes (p < 0.05). Upon co-stimulation, Uu8 and Up3 inhibited LPS-induced intracellular IL-1β (p < 0.001 and p < 0.05) and IL-8 in adult monocytes (p < 0.01), while LPS-induced neonatal cytokines were maintained or aggravated (p < 0.05). Conclusion: Our data demonstrate a considerable pro-inflammatory capacity of Ureaplasma isolates in human monocytes. Stimulating pro-inflammatory cytokine responses while hardly inducing immunomodulatory and anti-inflammatory cytokines, ureaplasmas might push monocyte immune responses toward pro-inflammation. Inhibition of LPS-induced cytokines in adult monocytes in contrast to sustained inflammation in term neonatal monocytes indicates a differential modulation of host immune responses to a second stimulus. Modification of TLR2 and TLR4 expression may shape host susceptibility to inflammation.}, language = {en} } @article{PagelTwisselmannRauschetal.2020, author = {Pagel, Julia and Twisselmann, Nele and Rausch, Tanja K. and Waschina, Silvio and Hartz, Annika and Steinbeis, Magdalena and Olbertz, Jonathan and Nagel, Kathrin and Steinmetz, Alena and Faust, Kirstin and Demmert, Martin and G{\"o}pel, Wolfgang and Herting, Egbert and Rupp, Jan and H{\"a}rtel, Christoph}, title = {Increased Regulatory T Cells Precede the Development of Bronchopulmonary Dysplasia in Preterm Infants}, series = {Frontiers in Immunology}, volume = {11}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2020.565257}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-212409}, year = {2020}, abstract = {Regulatory T cells (Tregs) are important for the ontogenetic control of immune activation and tissue damage in preterm infants. However, the role of Tregs for the development of bronchopulmonary dysplasia (BPD) is yet unclear. The aim of our study was to characterize CD4+ CD25+ forkhead box protein 3 (FoxP3)+ Tregs in peripheral blood of well-phenotyped preterm infants (n = 382; 23 + 0 - 36 + 6 weeks of gestational age) with a focus on the first 28 days of life and the clinical endpoint BPD (supplemental oxygen for longer than 28 days of age). In a subgroup of preterm infants, we characterized the immunological phenotype of Tregs (n = 23). The suppressive function of Tregs on CD4+CD25- T cells was compared in preterm, term and adult blood. We observed that extreme prematurity was associated with increased Treg frequencies which peaked in the second week of life. Independent of gestational age, increased Treg frequencies were noted to precede the development of BPD. The phenotype of preterm infant Tregs largely differed from adult Tregs and displayed an overall na{\"i}ve Treg population (CD45RA+/HLA-DR-/Helios+), especially in the first days of life. On day 7 of life, a more activated Treg phenotype pattern (CCR6+, HLA-DR+, and Ki-67+) was observed. Tregs of preterm neonates had a higher immunosuppressive capacity against CD4+CD25- T cells compared to the Treg compartment of term neonates and adults. In conclusion, our data suggest increased frequencies and functions of Tregs in preterm neonates which display a distinct phenotype with dynamic changes in the first weeks of life. Hence, the continued abundance of Tregs may contribute to sustained inflammation preceding the development of BPD. Functional analyses are needed in order to elucidate whether Tregs have potential as future target for diagnostics and therapeutics.}, language = {en} } @article{PellegrinoDelBufaloDeAngelisetal.2020, author = {Pellegrino, Marsha and Del Bufalo, Francesca and De Angelis, Biagio and Quintarelli, Concetta and Caruana, Ignazio and de Billy, Emmanuel}, title = {Manipulating the metabolism to improve the efficacy of CAR T-cell immunotherapy}, series = {Cells}, volume = {10}, journal = {Cells}, number = {1}, issn = {2073-4409}, doi = {10.3390/cells10010014}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220140}, year = {2020}, abstract = {The adoptive transfer of the chimeric antigen receptor (CAR) expressing T-cells has produced unprecedented successful results in the treatment of B-cell malignancies. However, the use of this technology in other malignancies remains less effective. In the setting of solid neoplasms, CAR T-cell metabolic fitness needs to be optimal to reach the tumor and execute their cytolytic function in an environment often hostile. It is now well established that both tumor and T cell metabolisms play critical roles in controlling the immune response by conditioning the tumor microenvironment and the fate and activity of the T cells. In this review, after a brief description of the tumoral and T cell metabolic reprogramming, we summarize the latest advances and new strategies that have been developed to improve the metabolic fitness and efficacy of CAR T-cell products.}, language = {en} } @article{HaarmannSchuhmannSilwedeletal.2019, author = {Haarmann, Axel and Schuhmann, Michael K. and Silwedel, Christine and Monoranu, Camelia-Maria and Stoll, Guido and Buttmann, Mathias}, title = {Human brain endothelial CXCR2 is inflammation-inducible and mediates CXCL5- and CXCL8-triggered paraendothelial barrier breakdown}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {3}, issn = {1422-0067}, doi = {10.3390/ijms20030602}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201297}, year = {2019}, abstract = {Chemokines (C-X-C) motif ligand (CXCL) 5 and 8 are overexpressed in patients with multiple sclerosis, where CXCL5 serum levels were shown to correlate with blood-brain barrier dysfunction as evidenced by gadolinium-enhanced magnetic resonance imaging. Here, we studied the potential role of CXCL5/CXCL8 receptor 2 (CXCR2) as a regulator of paraendothelial brain barrier function, using the well-characterized human cerebral microvascular endothelial cell line hCMEC/D3. Low basal CXCR2 mRNA and protein expression levels in hCMEC/D3 were found to strongly increase under inflammatory conditions. Correspondingly, immunohistochemistry of brain biopsies from two patients with active multiple sclerosis revealed upregulation of endothelial CXCR2 compared to healthy control tissue. Recombinant CXCL5 or CXCL8 rapidly and transiently activated Akt/protein kinase B in hCMEC/D3. This was followed by a redistribution of tight junction-associated protein zonula occludens-1 (ZO-1) and by the formation of actin stress fibers. Functionally, these morphological changes corresponded to a decrease of paracellular barrier function, as measured by a real-time electrical impedance-sensing system. Importantly, preincubation with the selective CXCR2 antagonist SB332235 partially prevented chemokine-induced disturbance of both tight junction morphology and function. We conclude that human brain endothelial CXCR2 may contribute to blood-brain barrier disturbance under inflammatory conditions with increased CXCL5 and CXCL8 expression, where CXCR2 may also represent a novel pharmacological target for blood-brain barrier stabilization.}, language = {en} } @article{EurichNitscheLauetal.2022, author = {Eurich, Benjamin and Nitsche, Catharina and Lau, Margot and Hanker, Britta and Spiegler, Juliane and Stichtenoth, Guido}, title = {Progressive respiratory insufficiency in a teenager with diaphragmatic hypomotility due to a novel combination of gliomedin gene variants}, series = {Children}, volume = {9}, journal = {Children}, number = {6}, issn = {2227-9067}, doi = {10.3390/children9060797}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275199}, year = {2022}, abstract = {Lethal congenital contracture syndrome 11 (LCCS11) is a form of arthrogryposis multiplex congenita (AMC) which is associated with mutations in the gliomedin gene (GLDN) and has been known to be severely life-shortening, mainly due to respiratory insufficiency. Patients with this condition have been predominantly treated by pediatricians as they usually do not survive beyond childhood. In this case report, we present a young adult who developed severe progressive respiratory insufficiency as a teenager due to diaphragmatic hypomotility and was diagnosed with LCCS11 following the discovery of compound heterozygous pathogenic variants in GLDN. This case demonstrates the importance of screening for neuromuscular diseases in well-child visits and follow-ups of patients at risk for gross and fine motor function developmental delay. It also underscores the significance of including LCCS11 and other axonopathies in the differential diagnosis of juvenile onset of respiratory insufficiency, highlights that patients with this condition may present to adult practitioners and questions whether the nomenclature of this condition with various phenotypes should be reconsidered due to the stigmatizing term 'lethal'.}, language = {en} } @article{FroehlichSchwaneckGernertetal.2020, author = {Froehlich, Matthias and Schwaneck, Eva C. and Gernert, Michael and Gadeholt, Ottar and Strunz, Patrick-Pascal and Morbach, Henner and Tony, Hans-Peter and Schmalzing, Marc}, title = {Autologous Stem Cell Transplantation in Common Variable Immunodeficiency: A Case of Successful Treatment of Severe Refractory Autoimmune Encephalitis}, series = {Frontiers in Immunology}, volume = {11}, journal = {Frontiers in Immunology}, number = {1317}, issn = {1664-3224}, doi = {10.3389/fimmu.2020.01317}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206972}, year = {2020}, abstract = {Common variable immunodeficiency (CVID) is the most common primary immunodeficiency in adults. It is associated with hypogammaglobulinemia, recurring infections and autoimmune phenomena. Treatment includes immunoglobulin substitution and immunosuppressants. Autoimmune neurological manifestations of CVID are rare and occur predominantly as granulomatous disease. We report the case of a 35-year-old woman with CVID who developed autoimmune encephalitis as demonstrated by double cerebral biopsy. Infectious or malignant causes could be excluded. Despite intensive immunosuppressive therapy with common regimens no significant improvement could be achieved. Ultimately, an autologous hematopoietic stem cell transplantation (HSCT) was performed, resulting in lasting complete remission of the encephalitis. To our knowledge, this is the first report of refractory autoimmune phenomena in CVID treated by autologous HSCT.}, language = {en} } @phdthesis{Aggar2024, author = {Aggar, Sara}, title = {Plastizit{\"a}t regulatorischer T-Zellen in Abh{\"a}ngigkeit des umgebenden Zytokinmilieus}, doi = {10.25972/OPUS-35187}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-351870}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Eine Dysbalance zwischen regulatorischen und proinflammatorischen T-Helferzellen kann zu Autoimmunerkrankungen f{\"u}hren. In dieser methodischen Arbeit wurde die Polarisierbarkeit von peripheren T-Lymphozyten durch verschiedene Zytokin-Stimuli untersucht. Hauptziel war es, CD4+CD25-CD127- Lymphozyten durch Stimulation mit einem IL-2 und TGFβ-beinhaltenden Zytokin-Cocktail (Treg-Cocktail) zu iTregs zu polarisieren und deren Suppressionsfunktion auf autologe Effektor-Leukozyten zu untersuchen. Es erfolgte eine Ph{\"a}notypisierung der PBMCs gesunder Probanden, insbesondere im Hinblick auf die Verteilung der T-Lymphozyten-Subpopulationen, deren Zytokinproduktion und FoxP3-Expression. Zudem wurden aus den PBMCs der Probanden Tregs (CD4+CD25+CD127low/-) sowie CD4+CD25-CD127- Zellen isoliert und deren Funktionsf{\"a}higkeit durch die Untersuchung ihrer Suppressionsfunktion auf autologe Effektor-Lymphozyten analysiert. Die Zellen wurden mittels verschiedener Zytokin-Cocktails in Richtung Treg sowie in Richtung Th17-Zellen polarisiert; anschließend wurde die Funktionsf{\"a}higkeit der polarisierten Zellen in Suppression-Assays gemessen. Wir konnten zeigen, dass die CD4+CD25+CD127low/- Zellen Tregs mit der F{\"a}higkeit zur Suppression der Proliferation autologer Effektor-Lymphozyten waren. Bei den CD4+CD25-CD127-Zellen handelte es sich um T-Lymphozyten ohne Suppressionsfunktion. Nach Stimulation der CD4+CD25-CD127-Zellen mit dem Treg-Cocktail zeigten die Zellen eine mit den Tregs vergleichbare Suppressionsfunktion. Mit dieser Studie haben wir eine aktuelle methodische Quelle f{\"u}r die Untersuchung von Ph{\"a}notyp und Funktion regulatorischer T-Zellen sowie f{\"u}r die Stimulation peripherer T-Lymphozyten hin zu Tregs geschaffen, die als Basis f{\"u}r Folgeversuche dienen soll, in denen Zellen von Patienten mit Autoimmunkrankheiten untersucht werden sollen. Da sich die Inflammation bei Autoimmunerkrankungen insbesondere in den betroffenen Geweben abspielt, w{\"a}re eine Studie anzustreben, in der aus dem Blut isolierte T-Lymphozyten den Zellen aus den entz{\"u}ndeten Geweben gegen{\"u}bergestellt werden. Erg{\"a}nzend sollte eine Ph{\"a}notypisierung der Tregs und der CD4+CD25-CD127- Zellen nach der Zytokin-Stimulation erfolgen. Zusammenfassend konnte die Plastizit{\"a}t peripherer T-Lymphozyten in Richtung Treg gezeigt werden. Besonders hervorzuheben ist die bislang wenig untersuchte Zellpopulation der CD4+CD25-CD127- Zellen, die eine vielversprechende Zellpopulation f{\"u}r die in vitro Induktion von Tregs darstellt.}, subject = {Regulatorischer T-Lymphozyt}, language = {de} } @article{GiansantiTheinertBoeingetal.2023, author = {Giansanti, Manuela and Theinert, Tobias and Boeing, Sarah Katharina and Haas, Dorothee and Schlegel, Paul-Gerhardt and Vacca, Paola and Nazio, Francesca and Caruana, Ignazio}, title = {Exploiting autophagy balance in T and NK cells as a new strategy to implement adoptive cell therapies}, series = {Molecular Cancer}, volume = {22}, journal = {Molecular Cancer}, doi = {10.1186/s12943-023-01893-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357515}, year = {2023}, abstract = {Autophagy is an essential cellular homeostasis pathway initiated by multiple stimuli ranging from nutrient deprivation to viral infection, playing a key role in human health and disease. At present, a growing number of evidence suggests a role of autophagy as a primitive innate immune form of defense for eukaryotic cells, interacting with components of innate immune signaling pathways and regulating thymic selection, antigen presentation, cytokine production and T/NK cell homeostasis. In cancer, autophagy is intimately involved in the immunological control of tumor progression and response to therapy. However, very little is known about the role and impact of autophagy in T and NK cells, the main players in the active fight against infections and tumors. Important questions are emerging: what role does autophagy play on T/NK cells? Could its modulation lead to any advantages? Could specific targeting of autophagy on tumor cells (blocking) and T/NK cells (activation) be a new intervention strategy? In this review, we debate preclinical studies that have identified autophagy as a key regulator of immune responses by modulating the functions of different immune cells and discuss the redundancy or diversity among the subpopulations of both T and NK cells in physiologic context and in cancer.}, language = {en} } @article{HeinemannStalpBonifacioetal.2023, author = {Heinemann, Anna Sophie and Stalp, Jan Lennart and Bonifacio, Jo{\~a}o Pedro Pereira and Silva, Filo and Willers, Maike and Heckmann, Julia and Fehlhaber, Beate and V{\"o}llger, Lena and Raafat, Dina and Normann, Nicole and Klos, Andreas and Hansen, Gesine and Schmolke, Mirco and Viemann, Dorothee}, title = {Silent neonatal influenza A virus infection primes systemic antimicrobial immunity}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1072142}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304782}, year = {2023}, abstract = {Infections with influenza A viruses (IAV) cause seasonal epidemics and global pandemics. The majority of these infections remain asymptomatic, especially among children below five years of age. Importantly, this is a time, when immunological imprinting takes place. Whether early-life infections with IAV affect the development of antimicrobial immunity is unknown. Using a preclinical mouse model, we demonstrate here that silent neonatal influenza infections have a remote beneficial impact on the later control of systemic juvenile-onset and adult-onset infections with an unrelated pathogen, Staphylococcus aureus, due to improved pathogen clearance and clinical resolution. Strategic vaccination with a live attenuated IAV vaccine elicited a similar protection phenotype. Mechanistically, the IAV priming effect primarily targets antimicrobial functions of the developing innate immune system including increased antimicrobial plasma activity and enhanced phagocyte functions and antigen-presenting properties at mucosal sites. Our results suggest a long-term benefit from an exposure to IAV during the neonatal phase, which might be exploited by strategic vaccination against influenza early in life to enforce the host's resistance to later bacterial infections.}, language = {en} } @article{DirksAndresPauletal.2023, author = {Dirks, Johannes and Andres, Oliver and Paul, Luisa and Manukjan, Georgi and Schulze, Harald and Morbach, Henner}, title = {IgD shapes the pre-immune na{\"i}ve B cell compartment in humans}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1096019}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304758}, year = {2023}, abstract = {B cell maturation and immunoglobulin (Ig) repertoire selection are governed by expression of a functional B cell receptor (BCR). Na{\"i}ve B cells co-express their BCR as IgM and IgD isotype. However, the role of the additionally expressed IgD on na{\"i}ve B cells is not known. Here we assessed the impact of IgD on na{\"i}ve B cell maturation and Ig repertoire selection in 8 individuals from 3 different families with heterozygous loss-of-function or loss-of expression mutations in IGHD. Although na{\"i}ve B cells from these individuals expressed IgM on their surface, the IGHD variant in heterozygous state entailed a chimeric situation by allelic exclusion with almost half of the na{\"i}ve B cell population lacking surface IgD expression. Flow cytometric analyses revealed a distinct phenotype of IgD-negative na{\"i}ve B cells with decreased expression of CD19, CD20 and CD21 as well as lower BAFF-R and integrin-β7 expression. IgD-negative B cells were less responsive in vitro after engaging the IgM-BCR, TLR7/9 or CD40 pathway. Additionally, a selective disadvantage of IgD-negative B cells within the T2 transitional and mature na{\"i}ve B cell compartment as well as reduced frequencies of IgMlo/- B cells within the mature na{\"i}ve B cell compartment lacking IgD were evident. RNA-Ig-seq of bulk sorted B cell populations showed an altered selection of distinct VH segments in the IgD-negative mature na{\"i}ve B cell population. We conclude that IgD expression on human na{\"i}ve B cells is redundant for generation of na{\"i}ve B cells in general, but further shapes the naive B cell compartment starting from T2 transitional B cells. Our observations suggest an unexpected role of IgD expression to be critical for selection of distinct Ig VH segments into the pre-immune Ig repertoire and for the survival of IgMlo/- na{\"i}ve B cells known to be enriched in poly-/autoreactive B cell clones.}, language = {en} } @article{vonLukowiczSchlegelHaerteletal.2021, author = {von Lukowicz, Hannah and Schlegel, Paul-Gerhardt and H{\"a}rtel, Christoph and Morbach, Henner and Haubitz, Imme and Wiegering, Verena}, title = {ESPED survey on newly diagnosed immune thrombocytopenia in childhood: how much treatment do we give?}, series = {Molecular and Cellular Pediatrics}, volume = {8}, journal = {Molecular and Cellular Pediatrics}, doi = {10.1186/s40348-021-00121-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-261832}, year = {2021}, abstract = {Background Immune thrombocytopenia (ITP) is an autoimmune disease associated with isolated thrombocytopenia, which is caused by an imbalance between platelet production and platelet destruction. Petechial and mucous membrane hemorrhages are characteristic of ITP, but life-threatening bleeding rarely occurs. Depending on the bleeding symptoms, ITP can be treated with glucocorticoids (GC), intravenous immunoglobulins (IVIG), or in severe cases, platelet transfusions. Mild bleeding does not necessarily require therapy. Using the German Surveillance Unit for rare Pediatric Diseases (ESPED) we conducted a prospective survey on ITP patients in all German Children's Hospitals between September 2018 and August 2019. We collected data on ITP, including the clinical course, therapy implementation recommendations (according to the Association of German Scientific Medical Societies guidelines), outcome, and influence of treatment regimens depending on the treating physician´s experience with ITP patients. Results Of the 287 recorded cases of children with ITP, 268 questionnaires were sent to the authors. Two hundred seventeen of the questionnaires fulfilled the inclusion criteria. ITP affected boys and girls similarly, and the median age of manifestation was 3.5 years. The main reasons for hospitalization were thrombocytopenia, bleeding signs, hematomas, and/or petechiae. Bleeding scores were ≤ 3 in 96\% of children, which corresponded to a low-to-moderately low risk of bleeding. No life-threatening bleeding was documented. The most common therapies were IVIG (n = 59), GC (n = 33), or a combination of these (n = 17). Blood products (i.e., red blood cells, platelet concentrate, and fresh frozen plasma) were given to 13 patients. Compared to the established guidelines, 67 patients were over-treated, and 2 patients were under-treated. Conclusions Adherence to German ITP treatment guidelines is currently limited. To improve patient safety and medical care, better medical training and dissemination of the guidelines are required in line with targeted analyses of patients with serious bleeding events to identify potential risk constellations.}, language = {en} } @article{PagottoSimeoneBroccoetal.2023, author = {Pagotto, Sara and Simeone, Pasquale and Brocco, Davide and Catitti, Giulia and De Bellis, Domenico and Vespa, Simone and Di Pietro, Natalia and Marinelli, Lisa and Di Stefano, Antonio and Veschi, Serena and De Lellis, Laura and Verginelli, Fabio and Kaitsas, Francesco and Iezzi, Manuela and Pandolfi, Assunta and Visone, Rosa and Tinari, Nicola and Caruana, Ignazio and Di Ianni, Mauro and Cama, Alessandro and Lanuti, Paola and Florio, Rosalba}, title = {CAR-T-derived extracellular vesicles: a promising development of CAR-T anti-tumor therapy}, series = {Cancers}, volume = {15}, journal = {Cancers}, number = {4}, issn = {2072-6694}, doi = {10.3390/cancers15041052}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304195}, year = {2023}, abstract = {Extracellular vesicles (EVs) are a heterogenous population of plasma membrane-surrounded particles that are released in the extracellular milieu by almost all types of living cells. EVs are key players in intercellular crosstalk, both locally and systemically, given that they deliver their cargoes (consisting of proteins, lipids, mRNAs, miRNAs, and DNA fragments) to target cells, crossing biological barriers. Those mechanisms further trigger a wide range of biological responses. Interestingly, EV phenotypes and cargoes and, therefore, their functions, stem from their specific parental cells. For these reasons, EVs have been proposed as promising candidates for EV-based, cell-free therapies. One of the new frontiers of cell-based immunotherapy for the fight against refractory neoplastic diseases is represented by genetically engineered chimeric antigen receptor T (CAR-T) lymphocytes, which in recent years have demonstrated their effectiveness by reaching commercialization and clinical application for some neoplastic diseases. CAR-T-derived EVs represent a recent promising development of CAR-T immunotherapy approaches. This crosscutting innovative strategy is designed to exploit the advantages of genetically engineered cell-based immunotherapy together with those of cell-free EVs, which in principle might be safer and more efficient in crossing biological and tumor-associated barriers. In this review, we underlined the potential of CAR-T-derived EVs as therapeutic agents in tumors.}, language = {en} } @phdthesis{Morper2023, author = {Morper, Lorenz}, title = {Ph{\"a}notypische Wirkung von PGE2 auf die TLR-vermittelte Ausreifung in-vitro-generierter monozytenderivierter dendritischer Zellen}, doi = {10.25972/OPUS-32964}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-329647}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Dendritische Zellen (DC) spielen eine Schl{\"u}sselrolle im Immunsystem. Sie dienen als professionelle antigenpr{\"a}sentierende Zellen und k{\"o}nnen eine antigenspezifische Immunantwort initiieren, indem sie naive T-Zellen primen. DC k{\"o}nnen auch verwendet werden, um T-Zellen im Kontext der onkologischen Immuntherapie zu stimulieren. In vitro k{\"o}nnen sie leicht aus Monozyten differenziert werden. Die daraus resultierenden unreifen DC k{\"o}nnen bereits Antigene phagozytieren und pr{\"a}sentieren, sie aktivieren jedoch noch keine Immunantwort solange keines der aufgenommenen Antigene als pathogen erkannt wird. Die Ausreifung einer unreifen, tolerogenen DC zu einer immunogenen reifen DC kann, neben anderen Methoden, durch einen Cocktail aus TLR-Liganden oder Zytokinen erreicht werden. Die Auswahl der Substanzen in diesem Cocktail bestimmt den Ph{\"a}notyp und die funktionellen Eigenschaften der resultierenden reifen DC. Einige der ben{\"o}tigten F{\"a}higkeiten der DC in der Tumorimmuntherapie, wo sie aus Patientenmonozyten generiert, mit Tumorantigen beladen und dem Patienten wieder zugef{\"u}hrt werden sollen, umfassen die Migration zu den T-Zell-Zonen der Lymphknoten, Antigenpr{\"a}sentation auf sowohl MHC-I- als auch MHC-II-Molek{\"u}len, Zytokinproduktion f{\"u}r die Direktion der T-Zell-Antwort wie IL-12p70, und die Expression von Oberfl{\"a}chenmarkern wie der kostimulatorischen Molek{\"u}le CD80 und CD86. In der Vergangenheit wurde gezeigt, dass durch Zugabe von Prostaglandin E2 (PGE2) zu einem Cocktail mit dem synthetischen TLR3-Liganden poly-I:C und dem TLR7/8-Liganden R848 (Resiquimod) sowohl eine gute migratorische F{\"a}higkeit als auch eine erh{\"o}hte IL-12p70-Produktion erreicht werden kann, w{\"a}hrend etwa die F{\"a}higkeit zur Antigen-Kreuzpr{\"a}sentation reduziert erschien. Anhand von Monozyten anonymer gesunder Spender beleuchtet diese Arbeit daher den Effekt von PGE2 auf monozytenderivierte DC n{\"a}her, indem seine konzentrationsabh{\"a}ngige Wirkung auf deren Ph{\"a}notyp untersucht wird. In den durchgef{\"u}hrten Versuchen wurde dabei die Expressionsdichte der Oberfl{\"a}chenmarker CD83, CD80 und CD86, HLA-DR und CCR7 sowie der monozyt{\"a}re Marker CD14 durchflusszytometrisch analysiert. Die Ergebnisse zeigen bei Exposition mit PGE2 dosisabh{\"a}ngig eine Heraufregulation von CD80, CD83, CD86 und CCR7 in der Population reifer DC, deren Maximum in unteren mikromolaren Konzentrationen erreicht wird. Gleichzeitig induzierte PGE2 dosisabh{\"a}ngig auch die Entstehung einer zweiten Zellpopulation mit anderen Eigenschaften, die stattdessen den monozyt{\"a}ren Marker CD14 re-exprimierte. Dies ist f{\"u}r k{\"u}nftige Studien eine interessante Beobachtung, da sie eine differenzierte Betrachtung beider resultierender Subpopulationen anregt.}, subject = {Prostaglandin E2}, language = {de} } @article{GlaserKernSpeeretal.2023, author = {Glaser, Kirsten and Kern, David and Speer, Christian P. and Schlegel, Nicolas and Schwab, Michael and Thome, Ulrich H. and H{\"a}rtel, Christoph and Wright, Clyde J.}, title = {Imbalanced inflammatory responses in preterm and term cord blood monocytes and expansion of the CD14\(^+\)CD16\(^+\) subset upon toll-like receptor stimulation}, series = {International Journal of Molecular Sciences}, volume = {24}, journal = {International Journal of Molecular Sciences}, number = {5}, issn = {1422-0067}, doi = {10.3390/ijms24054919}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311056}, year = {2023}, abstract = {Developmentally regulated features of innate immunity are thought to place preterm and term infants at risk of infection and inflammation-related morbidity. Underlying mechanisms are incompletely understood. Differences in monocyte function including toll-like receptor (TLR) expression and signaling have been discussed. Some studies point to generally impaired TLR signaling, others to differences in individual pathways. In the present study, we assessed mRNA and protein expression of pro- and anti-inflammatory cytokines in preterm and term cord blood (CB) monocytes compared with adult controls stimulated ex vivo with Pam3CSK4, zymosan, polyinosinic:polycytidylic acid, lipopolysaccharide, flagellin, and CpG oligonucleotide, which activate the TLR1/2, TLR2/6, TLR3, TLR4, TLR5, and TLR9 pathways, respectively. In parallel, frequencies of monocyte subsets, stimulus-driven TLR expression, and phosphorylation of TLR-associated signaling molecules were analyzed. Independent of stimulus, pro-inflammatory responses of term CB monocytes equaled adult controls. The same held true for preterm CB monocytes—except for lower IL-1β levels. In contrast, CB monocytes released lower amounts of anti-inflammatory IL-10 and IL-1ra, resulting in higher ratios of pro-inflammatory to anti-inflammatory cytokines. Phosphorylation of p65, p38, and ERK1/2 correlated with adult controls. However, stimulated CB samples stood out with higher frequencies of intermediate monocytes (CD14\(^+\)CD16\(^+\)). Both pro-inflammatory net effect and expansion of the intermediate subset were most pronounced upon stimulation with Pam3CSK4 (TLR1/2), zymosan (TR2/6), and lipopolysaccharide (TLR4). Our data demonstrate robust pro-inflammatory and yet attenuated anti-inflammatory responses in preterm and term CB monocytes, along with imbalanced cytokine ratios. Intermediate monocytes, a subset ascribed pro-inflammatory features, might participate in this inflammatory state.}, language = {en} } @article{BoeckelKarstenGoepeletal.2023, author = {Boeckel, Hannah and Karsten, Christian M. and G{\"o}pel, Wolfgang and Herting, Egbert and Rupp, Jan and H{\"a}rtel, Christoph and Hartz, Annika}, title = {Increased expression of anaphylatoxin C5a-receptor-1 in neutrophils and natural killer cells of preterm infants}, series = {International Journal of Molecular Sciences}, volume = {24}, journal = {International Journal of Molecular Sciences}, number = {12}, issn = {1422-0067}, doi = {10.3390/ijms241210321}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321196}, year = {2023}, abstract = {Preterm infants are susceptible to infection and their defense against pathogens relies largely on innate immunity. The role of the complement system for the immunological vulnerability of preterm infants is less understood. Anaphylatoxin C5a and its receptors C5aR1 and -2 are known to be involved in sepsis pathogenesis, with C5aR1 mainly exerting pro-inflammatory effects. Our explorative study aimed to determine age-dependent changes in the expression of C5aR1 and C5aR2 in neonatal immune cell subsets. Via flow cytometry, we analyzed the expression pattern of C5a receptors on immune cells isolated from peripheral blood of preterm infants (n = 32) compared to those of their mothers (n = 25). Term infants and healthy adults served as controls. Preterm infants had a higher intracellular expression of C5aR1 on neutrophils than control individuals. We also found a higher expression of C5aR1 on NK cells, particularly on the cytotoxic CD56\(^{dim}\) subset and the CD56\(^-\) subset. Immune phenotyping of other leukocyte subpopulations revealed no gestational-age-related differences for the expression of and C5aR2. Elevated expression of C5aR1 on neutrophils and NK cells in preterm infants may contribute to the phenomenon of "immunoparalysis" caused by complement activation or to sustained hyper-inflammatory states. Further functional analyses are needed to elucidate the underlying mechanisms.}, language = {en} } @article{SitterFroehlichKrankeetal.2023, author = {Sitter, Magdalena and Fr{\"o}hlich, Corinna and Kranke, Peter and Markus, Christian and W{\"o}ckel, Achim and Rehn, Monika and Bartmann, Catharina and Frieauff, Eric and Meybohm, Patrick and Pecks, Ulrich and R{\"o}der, Daniel}, title = {ECMO-Therapie bei COVID-19-ARDS in der Schwangerschaft erm{\"o}glicht den Erhalt einer Schwangerschaft mit termingerechter Entbindung}, series = {Die Anaesthesiologie}, volume = {72}, journal = {Die Anaesthesiologie}, number = {3}, doi = {10.1007/s00101-022-01232-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-346762}, pages = {166-170}, year = {2023}, abstract = {No abstract available.}, language = {de} } @article{SitterPecksRuedigeretal.2022, author = {Sitter, Magdalena and Pecks, Ulrich and R{\"u}diger, Mario and Friedrich, Sabine and Fill Malfertheiner, Sara and Hein, Alexander and K{\"o}nigbauer, Josefine T. and Becke-Jakob, Karin and Z{\"o}llkau, Janine and Ramsauer, Babett and Rathberger, Katharina and Pontones, Constanza A. and Kraft, Katrina and Meybohm, Patrick and H{\"a}rtel, Christoph and Kranke, Peter}, title = {Pregnant and postpartum women requiring intensive care treatment for COVID-19 — first data from the CRONOS-registry}, series = {Journal of Clinical Medicine}, volume = {11}, journal = {Journal of Clinical Medicine}, number = {3}, issn = {2077-0383}, doi = {10.3390/jcm11030701}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-255257}, year = {2022}, abstract = {(1) Background: Data on coronavirus 2 infection during pregnancy vary. We aimed to describe maternal characteristics and clinical presentation of SARS-CoV-2 positive women requiring intensive care treatment for COVID-19 during pregnancy and postpartum period based on data of a comprehensive German surveillance system in obstetric patients. (2) Methods: Data from COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS), a prospective multicenter registry for SARS-CoV-2 positive pregnant women, was analyzed with respect to ICU treatment. All women requiring intensive care treatment for COVID-19 were included and compared regarding maternal characteristics, course of disease, as well as maternal and neonatal outcomes. (3) Results: Of 2650 cases in CRONOS, 101 women (4\%) had a documented ICU stay. Median maternal age was 33 (IQR, 30-36) years. COVID-19 was diagnosed at a median gestational age of 33 (IQR, 28-35) weeks. As the most invasive form of COVID-19 treatment interventions, patients received either continuous monitoring of vital signs without further treatment requirement (n = 6), insufflation of oxygen (n = 30), non-invasive ventilation (n = 22), invasive ventilation (n = 28), or escalation to extracorporeal membrane oxygenation (n = 15). No significant clinical differences were identified between patients receiving different forms of ventilatory support for COVID-19. Prevalence of preterm delivery was significantly higher in women receiving invasive respiratory treatments. Four women died of COVID-19 and six fetuses were stillborn. (4) Conclusions: Our cohort shows that progression of COVID-19 is rare in pregnant and postpartum women treated in the ICU. Preterm birth rate is high and COVID-19 requiring respiratory support increases the risk of poor maternal and neonatal outcome.}, language = {en} } @phdthesis{Sevgin2023, author = {Sevgin, Semanur}, title = {Inad{\"a}quate Sinustachykardie: Kardiovaskul{\"a}re Risikostratifizierung und Therapiekontrolle mittels Langzeit-EKG Daten von Jugendlichen}, doi = {10.25972/OPUS-33014}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-330148}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Inappropriate sinus tachycardia (IST) is a common disease of the autonomic nervous system in children and adults. Diagnosis and treatment of IST in adolescents is not well defined. In this retrospective study, we tested our hypothesis regarding autonomic dysfunction in childhood by analyzing 24-h heart rate variability (HRV) in 479 children, with a mean age of 13.7 ± 2.1 years, who were referred to the outpatient clinic in the Pediatrics Department within the last 15 years. Seventy-four adolescents with a mean 24-h heart rate ≥ 95 bpm (our cut-off for an IST based upon 66 healthy controls) were deemed to have IST. We found the risk of IST to be high in adolescents with attention deficit disorder (OR = 3.5,p<0.001), pre-hypertension (OR = 2.5, p = 0.043) and hypertension (OR = 2.1,p = 0.02); insignificantly enhanced in children with short stature (OR = 1.9,p = 0.19), surgically-treated congenital heart disease (OR = 1.4,p = 0.51) and obesity without hypertension (OR = 1.4;p = 0.25); and negligible in adolescents with anorexia nervosa (OR = 0.3, p = 0.26) and constitutional thinness (OR = 0.9,p = 0.89). IST was associated with a significant decrease in global HRV and elevated blood pressures, indicating an enhanced cardiovascular risk. Methylphenidate did not increase 24-h heart rates, whereas omega-3 fatty acid supplementation significantly decreased elevated heart rates and increased HRV in adolescents with IST. In this retrospective analysis, 15.4\% of adolescents suffered from IST with a 24-h heart rate ≥ 95 bpm, predominately due to attention deficit disorder and hypertension.}, subject = {HRV}, language = {de} } @phdthesis{Peter2024, author = {Peter, Lisa Susanne}, title = {Chronische Graft-versus-Host-Erkrankung im p{\"a}diatrischen Setting - Identifikation von Charakteristika mit Fokus auf die Immunrekonstitution dendritischer Zellen}, doi = {10.25972/OPUS-34954}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-349546}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Die cGvHD ist eine relevante Komplikation der aHSCT. Sie hat Einfluss auf die Morbidit{\"a}t und Mortalit{\"a}t nach der aHSCT. Die genaue Pathogenese ist unbekannt. Ein Einfluss dendritscher Zellen als Schl{\"u}sselzellen immunologischer Prozesse auf die Entstehung einer cGvHD ist wahrscheinlich. In dieser Studie erfassten wir patient:innen und aHSCT-bezogene Daten 61 stammzelltransplantierter Kinder und Jugendlicher sowie deren m{\"o}glichen Einfluss auf das Auftreten einer cGvHD. Zudem wurde die Rekonstitution der Immunzellen, insbesondere der DCs, nach der aHSCT evaluiert. Die Rekonstitution der Lymphozyten sowie die Zytokinexpression der T-Zellen w{\"a}hrend der Rekonstitution verhielt sich {\"a}hnlich zu vorherigen Studien. Signifikante Unterschiede zwischen Patient:innen mit oder ohne cGvHD zeigten sich nicht konsistent. Die Rekonstitution der DCs erfolgte innerhalb von 60-100 Tagen. Stabile Werte zeigten sich jedoch fr{\"u}hestens ein Jahr nach der aHSCT. W{\"a}hrend des Engraftments war der Anteil CCR7+ DCs bei Patient:innen erh{\"o}ht, die eine TBI erhalten hatten. Ein hoher Anteil CCR7+ DCs wirkte sich zu jedem Zeitpunkt positiv auf das Gesamt{\"u}berleben aus. Trat eine h{\"o}hergradige aGvHD auf, konnte eine verminderte absolute und relative Zellzahl 60-365 Tage nach der aHSCT f{\"u}r DCs insgesamt und mDCs erfasst werden, f{\"u}r pDCs 60-100 Tage nach aHCST. Zwischen der Rekonstitution der DCs und dem Auftreten einer cGvHD konnten wir vier Korrelationen beobachten. Der absolute und relative Zahlenwert an mDCs war w{\"a}hrend des Engraftments bis Tag 60-100 vermindert. Der absolute und relative Zahlenwert an DCs insgesamt war ab Tag 101-365 vermindert. Ein erh{\"o}hter Anteil an pDCs konnte ab Tag 101-365 sowie zu Beginn einer cGvHD bestimmt werden. Der Anteil monozyt{\"a}rer DCs war ab Tag 60-100 erh{\"o}ht. Die Pathogenese der cGvHD bleibt weiter teilweise unklar. Unsere Daten suggerieren einen Einfluss der DCs auf die Entstehung einer cGvHD.}, subject = {Dendritische Zelle}, language = {de} } @article{BartholdJurkutatGoetzetal.2023, author = {Barthold, Martina and Jurkutat, Anne and Goetz, Regina and Schubring, Lucia and Spiegler, Juliane and Fries, Ann-Sophie and Kiesel, Lucia and Klepper, Joerg}, title = {Timing of ketogenic dietary therapy (KDT) introduction and its impact on cognitive profiles in children with Glut1-DS — a preliminary study}, series = {Children}, volume = {10}, journal = {Children}, number = {4}, issn = {2227-9067}, doi = {10.3390/children10040681}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313569}, year = {2023}, abstract = {The aim of this research was to characterize cognitive abilities in patients with Glut1-Deficiency syndrome (Glut1DS) following ketogenic diet therapy (KDT). Methods: The cognitive profiles of eight children were assessed using the Wechsler Intelligence Scale (WISC-IV). The effect of ketogenic diet therapy (KDT) on individual subareas of intelligence was analyzed considering the potential influence of speech motor impairments. Results: Patients with Glut1DS showed a wide range of cognitive performance levels. Some participants showed statistically and clinically significant discrepancies between individual subdomains of intelligence. Both variables, KDT initiation as well as duration, had a positive effect on the overall IQ score. Significant correlations were partially found between the time of KDT initiation and the level of IQ scores, depending on the presence of expressive language test demands of the respective subtests of the WISC-IV. Accordingly, the participants benefited les in the linguistic cognitive domain. The discrepancies in cognitive performance profiles of patients with Glut1DS can be attributed to the possibility of a negative distortion of the results due to the influence of speech motor impairments. Conclusions: The individual access skills of test persons should be more strongly considered in test procedures for the assessment of intelligence to reduce the negative influence of motor deficits on test performance. Specific characterization and systematization of the speech disorder are indispensable for determining the severity of speech motor impairment in Glut1DS. Therefore, a stronger focus on dysarthria during diagnosis and therapy is necessary.}, language = {en} } @phdthesis{Lager2024, author = {Lager, Johanna}, title = {Expression immunmodulierende Marker in Zusammenhang mit Immuntherapie bei kindlichen Hirntumoren}, doi = {10.25972/OPUS-35220}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-352202}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2024}, abstract = {Atypische teratoide Rhabdoidtumore sind trotz Aussch{\"o}pfen der multimodalen Therapieoptionen weiterhin mit einer schlechten Prognose belastet. Gr{\"u}nde hierf{\"u}r liegen in den oftmals unzureichenden Resektionsm{\"o}glichkeiten, dem jungen Erkrankungsalter der PatientInnen und der Resistenz der Tumorzellen gegen{\"u}ber Chemotherapeutika (Fr{\"u}hwald et al. 2020; Egiz et al. 2022; Richards et al. 2019). Gerade deshalb versucht man durch die aktuelle Forschung zu kindlichen Hirntumoren mit Immuntherapie ein besseres Outcome zu erreichen. Wichtige Grundlagen hierzu sind durch diese Arbeit dargestellt worden. Erstmals wurde gezeigt, dass Tumorzellen der AT/RT sowohl HLA-Klasse I und -Klasse II Antigene pr{\"a}sentieren. Es wurde außerdem die Expression von PD-L1 nachgewiesen. Des Weiteren konnte die Anwesenheit von Immunzellen durch den Nachweis CD 3+ Zellen bewiesen werden. Insgesamt zeigte sich eine große Heterogenit{\"a}t innerhalb des einzelnen und unter den verschiedenen Tumoren. Es zeigte sich eine negative Korrelation zwischen der Expression von MHC I und CD 3+ Zellen, welche insgesamt f{\"u}r einen Tumor Escape Mechanismus sprechen k{\"o}nnte, wie er bereits bei Glioblastomen nachgewiesen wurde (Bagley et al. 2018; Marcu et al. 2021). Es sollte eine Ausweitung der hier begonnen Forschung mit Einbeziehung der personenbezogenen Daten und Vergr{\"o}ßerung der untersuchten Fallzahl erfolgen.}, subject = {Immuntherapie}, language = {de} } @article{HaakeHaackSchaeferetal.2023, author = {Haake, Markus and Haack, Beatrice and Sch{\"a}fer, Tina and Harter, Patrick N. and Mattavelli, Greta and Eiring, Patrick and Vashist, Neha and Wedekink, Florian and Genssler, Sabrina and Fischer, Birgitt and Dahlhoff, Julia and Mokhtari, Fatemeh and Kuzkina, Anastasia and Welters, Marij J. P. and Benz, Tamara M. and Sorger, Lena and Thiemann, Vincent and Almanzar, Giovanni and Selle, Martina and Thein, Klara and Sp{\"a}th, Jacob and Gonzalez, Maria Cecilia and Reitinger, Carmen and Ipsen-Escobedo, Andrea and Wistuba-Hamprecht, Kilian and Eichler, Kristin and Filipski, Katharina and Zeiner, Pia S. and Beschorner, Rudi and Goedemans, Renske and Gogolla, Falk Hagen and Hackl, Hubert and Rooswinkel, Rogier W. and Thiem, Alexander and Romer Roche, Paula and Joshi, Hemant and P{\"u}hringer, Dirk and W{\"o}ckel, Achim and Diessner, Joachim E. and R{\"u}diger, Manfred and Leo, Eugen and Cheng, Phil F. and Levesque, Mitchell P. and Goebeler, Matthias and Sauer, Markus and Nimmerjahn, Falk and Schuberth-Wagner, Christine and Felten, Stefanie von and Mittelbronn, Michel and Mehling, Matthias and Beilhack, Andreas and van der Burg, Sjoerd H. and Riedel, Angela and Weide, Benjamin and Dummer, Reinhard and Wischhusen, J{\"o}rg}, title = {Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment}, series = {Nature Communications}, volume = {14}, journal = {Nature Communications}, doi = {10.1038/s41467-023-39817-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357333}, year = {2023}, abstract = {Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don't respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.}, language = {en} } @misc{DietzKudsiGarciaUrenaetal.2021, author = {Dietz, Ulrich A. and Kudsi, O. Yusef and Garcia-Ure{\~n}a, Miguel and Baur, Johannes and Ramser, Michaela and Maksimovic, Sladjana and Keller, Nicola and D{\"o}rfer, J{\"o}rg and Eisner, Lukas and Wiegering, Armin}, title = {Erratum to: Robotic hernia repair III. English version}, series = {Der Chirurg}, volume = {92}, journal = {Der Chirurg}, number = {Suppl 1}, doi = {10.1007/s00104-021-01564-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-329360}, pages = {40}, year = {2021}, abstract = {No abstract available.}, language = {en} } @article{DirksFischerHaaseetal.2021, author = {Dirks, Johannes and Fischer, Jonas and Haase, Gabriele and Holl-Wieden, Annette and Hofmann, Christine and Girschick, Hermann and Morbach, Henner}, title = {CD21\(^{lo/-}\)CD27\(^-\)IgM\(^-\) Double-Negative B Cells Accumulate in the Joints of Patients With Antinuclear Antibody-Positive Juvenile Idiopathic Arthritis}, series = {Frontiers in Pediatrics}, volume = {9}, journal = {Frontiers in Pediatrics}, issn = {2296-2360}, doi = {10.3389/fped.2021.635815}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236286}, year = {2021}, abstract = {Juvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of diseases. The appearance of antinuclear antibodies (ANAs) in almost half of the patients suggests B cell dysregulation as a distinct pathomechanism in these patients. Additionally, ANAs were considered potential biomarkers encompassing a clinically homogenous subgroup of JIA patients. However, in ANA+ JIA patients, the site of dysregulated B cell activation as well as the B cell subsets involved in this process is still unknown. Hence, in this cross-sectional study, we aimed in an explorative approach at characterizing potential divergences in B cell differentiation in ANA+ JIA patients by assessing the distribution of peripheral blood (PB) and synovial fluid (SF) B cell subpopulations using flow cytometry. The frequency of transitional as well as switched-memory B cells was higher in PB of JIA patients than in healthy controls. There were no differences in the distribution of B cell subsets between ANA- and ANA+ patients in PB. However, the composition of SF B cells was different between ANA- and ANA+ patients with increased frequencies of CD21\(^{lo/-}\)CD27\(^-\)IgM\(^-\) "double negative" (DN) B cells in the latter. DN B cells might be a characteristic subset expanding in the joints of ANA+ JIA patients and are potentially involved in the antinuclear immune response in these patients. The results of our explorative study might foster further research dissecting the pathogenesis of ANA+ JIA patients.}, language = {en} } @article{HedrichMorbachReiseretal.2020, author = {Hedrich, Christian M. and Morbach, Henner and Reiser, Christiane and Girschick, Hermann J.}, title = {New Insights into Adult and Paediatric Chronic Non-bacterial Osteomyelitis CNO}, series = {Current Rheumatology Reports}, volume = {22}, journal = {Current Rheumatology Reports}, issn = {1523-3774}, doi = {10.1007/s11926-020-00928-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232636}, year = {2020}, abstract = {Purpose of Review To describe in detail the clinical synopsis and pathophysiology of chronic non-bacterial osteomyelitis and SAPHO syndrome. Recent Findings Chronic non-bacterial osteomyelitis (CNO) has been identified as a disease entity for almost 50 years. This inflammatory bone disorder is characterized by osteolytic as well as hyperostotic/osteosclerotic lesions. It is chronic in nature, but it can present with episodic flairs and phases of remission, which have led to the denomination "chronic recurrent osteomyelitis", with its severe multifocal form "chronic recurrent multifocal osteomyelitis" (CRMO). For almost three decades, an infectious aetiology had been considered, since especially Propionibacterium acnes had been isolated from bone lesions of individual patients. However, this concept has been challenged since long-term antibiotic therapy did not alter the course of disease and modern microbiological techniques (including PCR) failed to confirm bone infection as an underlying cause. Over recent years, a profound dysregulation of cytokine expression profiles has been demonstrated in innate immune cells of CNO patients. A hallmark of monocytes from CNO patients is the failure to produce immune regulatory cytokines interleukin-10 (IL-10) and IL-19, which have been linked with genetic and epigenetic alterations. Subsequently, a significant upregulation of pro-inflammatory, NLRP3 inflammasome-dependent cytokines (IL-1β and TNF-α), has been demonstrated. Summary The current knowledge on CNO, the underlying molecular pathophysiology, and modern imaging strategies are summarized; differential diagnoses, treatment options, outcome measures, as well as quality of life studies are discussed.}, language = {en} } @article{KrakowCrescimoneBartelsetal.2019, author = {Krakow, S{\"o}ren and Crescimone, Marie L. and Bartels, Charlotte and Wiegering, Verena and Eyrich, Matthias and Schlegel, Paul G. and W{\"o}lfl, Matthias}, title = {Re-expression of CD14 in response to a combined IL-10/TLR stimulus defines monocyte-derived cells with an immunoregulatory phenotype}, series = {Frontiers in Immunology}, volume = {10}, journal = {Frontiers in Immunology}, number = {1484}, doi = {10.3389/fimmu.2019.01484}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201537}, year = {2019}, abstract = {Interleukin 10 is a central regulator of the antigen-presenting function of myeloid cells. It exerts immunomodulatory effects in vivo and induces a regulatory phenotype in monocyte-derived cells in vitro. We analyzed phenotype and function of monocytic cells in vitro in relation to the cytokine milieu and the timing of TLR-based activation. In GM-CSF/IL-4 cultured human monocytic cells, we identified two, mutually exclusive cell populations arising from undifferentiated cells: CD83\(^+\) fully activated dendritic cells and CD14\(^+\) macrophage like cells. Re-expression of CD14 occurs primarily after a sequential trigger with a TLR signal following IL-10 preincubation. This cell population with re-expressed CD14 greatly differs in phenotype and function from the CD83+ cells. Detailed analysis of individual subpopulations reveals that exogenous IL-10 is critical for inducing the shift toward the CD14\(^+\) population, but does not affect individual changes in marker expression or cell function in most cases. Thus, plasticity of CD14 expression, defining a subset of immunoregulatory cells, is highly relevant for the composition of cellular products (such as DC vaccines) as it affects the function of the total product.}, language = {en} } @article{FischerDirksKlaussneretal.2022, author = {Fischer, Jonas and Dirks, Johannes and Klaussner, Julia and Haase, Gabriele and Holl-Wieden, Annette and Hofmann, Christine and Hackenberg, Stephan and Girschick, Hermann and Morbach, Henner}, title = {Effect of clonally expanded PD-1\(^h\)\(^i\)\(^g\)\(^h\) CXCR5-CD4+ peripheral T Helper cells on B cell differentiation in the joints of patients with antinuclear antibody-positive juvenile idiopathic arthritis}, series = {Arthritis \& Rheumatology}, volume = {74}, journal = {Arthritis \& Rheumatology}, number = {1}, doi = {10.1002/art.41913}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-256607}, pages = {150-162}, year = {2022}, abstract = {Objective Antinuclear antibody (ANA)-positive juvenile idiopathic arthritis (JIA) is characterized by synovial B cell hyperactivity, but the precise role of CD4+ T cells in promoting local B cell activation is unknown. This study was undertaken to determine the phenotype and function of synovial CD4+ T cells that promote aberrant B cell activation in JIA. Methods Flow cytometry was performed to compare the phenotype and cytokine patterns of PD-1\(^h\)\(^i\)\(^g\)\(^h\)CD4+ T cells in the synovial fluid (SF) of patients with JIA and T follicular helper cells in the tonsils of control individuals. TCRVB next-generation sequencing was used to analyze T cell subsets for signs of clonal expansion. The functional impact of these T cell subsets on B cells was examined in cocultures in vitro. Results Multidimensional flow cytometry revealed the expansion of interleukin-21 (IL-21) and interferon-γ (IFNγ)-coexpressing PD-1\(^h\)\(^i\)\(^g\)\(^h\)CXCR5-HLA-DR+CD4+ T cells that accumulate in the joints of ANA-positive JIA patients. These T cells exhibited signs of clonal expansion with restricted T cell receptor clonotypes. The phenotype resembled peripheral T helper (Tph) cells with an extrafollicular chemokine receptor pattern and high T-bet and B lymphocyte-induced maturation protein 1 expression, but low B cell lymphoma 6 expression. SF Tph cells, by provision of IL-21 and IFNy, skewed B cell differentiation toward a CD21\(^l\)\(^o\)\(^w\)\(^/\)\(^-\)CD11c+ phenotype in vitro. Additionally, SF Tph cell frequencies correlated with the appearance of SF CD21\(^l\)\(^o\)\(^w\)\(^/\)\(^-\)CD11c+CD27-IgM- double-negative (DN) B cells in situ.}, language = {en} } @article{SilwedelSpeerHaarmannetal.2019, author = {Silwedel, Christine and Speer, Christian P. and Haarmann, Axel and Fehrholz, Markus and Claus, Heike and Schlegel, Nicolas and Glaser, Kirsten}, title = {Ureaplasma species modulate cytokine and chemokine responses in human brain microvascular endothelial cells}, series = {International Journal of Molecular Science}, volume = {20}, journal = {International Journal of Molecular Science}, number = {14}, issn = {1422-0067}, doi = {10.3390/ijms20143583}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201848}, year = {2019}, abstract = {Ureaplasma species are common colonizers of the adult genitourinary tract and often considered as low-virulence commensals. Intraamniotic Ureaplasma infections, however, facilitate chorioamnionitis and preterm birth, and cases of Ureaplasma-induced neonatal sepsis, pneumonia, and meningitis raise a growing awareness of their clinical relevance. In vitro studies are scarce but demonstrate distinct Ureaplasma-driven impacts on immune mechanisms. The current study addressed cytokine and chemokine responses upon exposure of native or lipopolysaccharide (LPS) co-stimulated human brain microvascular endothelial cells (HBMEC) to Ureaplasma urealyticum or U. parvum, using qRT-PCR, RNA sequencing, multi-analyte immunoassay, and flow cytometry. Ureaplasma exposure in native HBMEC reduced monocyte chemoattractant protein (MCP)-3 mRNA expression (p < 0.01, vs. broth). In co-stimulated HBMEC, Ureaplasma spp. attenuated LPS-evoked mRNA responses for C-X-C chemokine ligand 5, MCP-1, and MCP-3 (p < 0.05, vs. LPS) and mitigated LPS-driven interleukin (IL)-1α protein secretion, as well as IL-8 mRNA and protein responses (p < 0.05). Furthermore, Ureaplasma isolates increased C-X-C chemokine receptor 4 mRNA levels in native and LPS co-stimulated HBMEC (p < 0.05). The presented results may imply immunomodulatory capacities of Ureaplasma spp. which may ultimately promote chronic colonization and long-term neuroinflammation.}, language = {en} } @article{SpringerHeldMengolietal.2021, author = {Springer, Jan and Held, J{\"u}rgen and Mengoli, Carlo and Schlegel, Paul Gerhardt and Gamon, Florian and Tr{\"a}ger, Johannes and Kurzai, Oliver and Einsele, Hermann and Loeffler, Juergen and Eyrich, Matthias}, title = {Diagnostic performance of (1→3)-β-D-glucan alone and in combination with aspergillus PCR and galactomannan in serum of pediatric patients after allogeneic hematopoietic stem cell transplantation}, series = {Journal of Fungi}, volume = {7}, journal = {Journal of Fungi}, number = {3}, issn = {2309-608X}, doi = {10.3390/jof7030238}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-234179}, year = {2021}, abstract = {Data on biomarker-assisted diagnosis of invasive aspergillosis (IA) in pediatric patients is scarce. Therefore, we conducted a cohort study over two years including 404 serum specimens of 26 pediatric patients after allogeneic hematopoietic stem cell transplantation (alloSCT). Sera were tested prospectively twice weekly for Aspergillus-specific DNA, galactomannan (GM), and retrospectively for (1→3)-β-D-glucan (BDG). Three probable IA and two possible invasive fungal disease (IFD) cases were identified using the European Organization for Research and Treatment of Cancer and the Mycoses Study Group (EORTC/MSGERC) 2019 consensus definitions. Sensitivity and specificity for diagnosis of probable IA and possible IFD was 80\% (95\% confidential interval (CI): 28-99\%) and 55\% (95\% CI: 32-77\%) for BDG, 40\% (95\% CI: 5-85\%) and 100\% (95\% CI: 83-100\%) for GM, and 60\% (95\% CI: 15-95\%) and 95\% (95\% CI: 75-100\%) for Aspergillus-specific real-time PCR. However, sensitivities have to be interpreted with great caution due to the limited number of IA cases. Interestingly, the low specificity of BDG was largely caused by false-positive BDG results that clustered around the date of alloSCT. The following strategies were able to increase BDG specificity: two consecutive positive BDG tests for diagnosis (specificity 80\% (95\% CI: 56-94\%)); using an optimized cutoff value of 306 pg/mL (specificity 90\% (95\% CI: 68-99\%)) and testing BDG only after the acute posttransplant phase. In summary, BDG can help to diagnose IA in pediatric alloSCT recipients. However, due to the poor specificity either an increased cutoff value should be utilized or BDG results should be confirmed by an alternative Aspergillus assay.}, language = {en} } @article{BohnertMonoranuSiauwetal.2020, author = {Bohnert, S. and Monoranu, C. - M. and Siauw, C. and Al-Tinawi, F. and Bohnert, M.}, title = {T{\"o}dliche Hirnmassenblutung infolge Vitamin-K-Mangels bei einem 9 Wochen alten S{\"a}ugling}, series = {Rechtsmedizin}, volume = {30}, journal = {Rechtsmedizin}, issn = {0937-9819}, doi = {10.1007/s00194-020-00387-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232475}, pages = {175-179}, year = {2020}, abstract = {Intrakranielle Blutungen sind im S{\"a}uglingsalter seltene, aber lebensbedrohende Ereignisse. Neben Gef{\"a}ßmissbildungen, Stoffwechseldefekten sowie St{\"o}rungen der Blutgerinnung kommen v. a. nichtakzidentielle Traumata, Sch{\"u}tteltrauma in Betracht. Die klinische Diagnostik umfasst hinsichtlich der Blutungsgenese neben Sonographie und MRT als apparatives Verfahren auch eine Fundoskopie sowie laborchemische Analysen, insbesondere der Gerinnungsparameter. F{\"u}r die Blutgerinnung ist das fettl{\"o}sliche Vitamin K essenziell: Fr{\"u}he, klassische und sp{\"a}te Vitamin-K-Mangel-Blutungen werden dabei unterschieden. Um ein geh{\"a}uftes Wiederauftreten von Vitamin-K-Mangel-Blutungen bei Neugeborenen und jungen S{\"a}uglingen zu verhindern, bedarf es einer hinreichenden Aufkl{\"a}rung der Eltern. Eine Verweigerung der Prophylaxe scheint Folge einer weltanschaulich begr{\"u}ndeten Ablehnung der Schulmedizin und ein zunehmendes Ph{\"a}nomen in wohlhabenden Industriel{\"a}ndern zu sein.}, language = {de} } @article{StrengGoettlerHaerleinetal.2019, author = {Streng, Andrea and Goettler, David and Haerlein, Miriam and Lehmann, Lisa and Ulrich, Kristina and Prifert, Christiane and Krempl, Christine and Weißbrich, Benedikt and Liese, Johannes G.}, title = {Spread and clinical severity of respiratory syncytial virus A genotype ON1 in Germany, 2011-2017}, series = {BMC Infectious Diseases}, volume = {19}, journal = {BMC Infectious Diseases}, doi = {10.1186/s12879-019-4266-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201516}, pages = {613}, year = {2019}, abstract = {Background The Respiratory Syncytial Virus (RSV) A genotype ON1, which was first detected in Ontario (Canada) in 2010/11, appeared in Germany in 2011/12. Preliminary observations suggested a higher clinical severity in children infected with this new genotype. We investigated spread and disease severity of RSV-A ON1 in pediatric in- and outpatient settings. Methods During 2010/11 to 2016/17, clinical characteristics and respiratory samples from children with acute respiratory tract infections (RTI) were obtained from ongoing surveillance studies in 33 pediatric practices (PP), one pediatric hospital ward (PW) and 23 pediatric intensive care units (PICU) in Germany. RSV was detected in the respiratory samples by PCR; genotypes were identified by sequencing. Within each setting, clinical severity markers were compared between RSV-A ON1 and RSV-A non-ON1 genotypes. Results A total of 603 children with RSV-RTI were included (132 children in PP, 288 in PW, and 183 in PICU). Of these children, 341 (56.6\%) were infected with RSV-A, 235 (39.0\%) with RSV-B, and one child (0.2\%) with both RSV-A and RSV-B; in 26 (4.3\%) children, the subtype could not be identified. In the 341 RSV-A positive samples, genotype ON1 was detected in 247 (72.4\%), NA1 in 92 (26.9\%), and GA5 in 2 children (0.6\%). RSV-A ON1, rarely observed in 2011/12, was the predominant RSV-A genotype in all settings by 2012/13 and remained predominant until 2016/17. Children in PP or PW infected with RSV-A ON1 did not show a more severe clinical course of disease compared with RSV-A non-ON1 infections. In the PICU group, hospital stay was one day longer (median 8 days, inter-quartile range (IQR) 7-12 vs. 7 days, IQR 5-9; p = 0.02) and duration of oxygen treatment two days longer (median 6 days, IQR 4-9 vs. 4 days, IQR 2-6; p = 0.03) for children infected with RSV-A ON1. Conclusions In children, RSV-A ON1 largely replaced RSV-A non-ON1 genotypes within two seasons and remained the predominant RSV-A genotype in Germany during subsequent seasons. A higher clinical severity of RSV-A ON1 was observed within the group of children receiving PICU treatment, whereas in other settings clinical severity of RSV-A ON1 and non-ON1 genotypes was largely similar.}, language = {en} } @article{GlaserSpeerWright2020, author = {Glaser, Kirsten and Speer, Christian P. and Wright, Clyde J.}, title = {Fine tuning non-invasive respiratory support to prevent lung injury in the extremely premature infant}, series = {Frontiers in Pediatrics}, volume = {7}, journal = {Frontiers in Pediatrics}, issn = {2296-2360}, doi = {10.3389/fped.2019.00544}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193762}, year = {2020}, abstract = {Within the last decades, therapeutic advances, such as antenatal corticosteroids, surfactant replacement, monitored administration of supplemental oxygen, and sophisticated ventilatory support have significantly improved the survival of extremely premature infants. In contrast, the incidence of some neonatal morbidities has not declined. Rates of bronchopulmonary dysplasia (BPD) remain high and have prompted neonatologists to seek effective strategies of non-invasive respiratory support in high risk infants in order to avoid harmful effects associated with invasive mechanical ventilation. There has been a stepwise replacement of invasive mechanical ventilation by early continuous positive airway pressure (CPAP) as the preferred strategy for initial stabilization and for early respiratory support of the premature infant and management of respiratory distress syndrome. However, the vast majority of high risk babies are mechanically ventilated at least once during their NICU stay. Adjunctive therapies aiming at the prevention of CPAP failure and the support of functional residual capacity have been introduced into clinical practice, including alternative techniques of administering surfactant as well as non-invasive ventilation approaches. In contrast, the strategy of applying sustained lung inflations in the delivery room has recently been abandoned due to evidence of higher rates of death within the first 48 h of life.}, language = {en} } @article{FortmannDammannHumbergetal.2021, author = {Fortmann, Ingmar and Dammann, Marie-Theres and Humberg, Alexander and Siller, Bastian and Stichtenoth, Guido and Engels, Geraldine and Marißen, Janina and Faust, Kirstin and Hanke, Kathrin and Goedicke-Fritz, Sybelle and Derouet, Christoph and Meyer, Sascha and Stutz, Regine and Kaiser, Elisabeth and Herting, Egbert and G{\"o}pel, Wolfgang and H{\"a}rtel, Christoph and Zemlin, Michael}, title = {Five year follow up of extremely low gestational age infants after timely or delayed administration of routine vaccinations}, series = {Vaccines}, volume = {9}, journal = {Vaccines}, number = {5}, issn = {2076-393X}, doi = {10.3390/vaccines9050493}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239592}, year = {2021}, abstract = {This study is aimed at detecting the rate of untimely immunization in a large cohort of extremely low gestational age neonates (ELGANs) of the German Neonatal Network (GNN) and at addressing risk factors for delayed vaccination and associated long-term consequences. We performed an observational study of the GNN between 1st January 2010 and 31st December 2019. The immunization status for the hexavalent and pneumococcal immunization was evaluated in n = 8401 preterm infants <29 weeks of gestation. Univariate analysis and logistic/linear regression models were used to identify risk factors for vaccination delay and outcomes at a 5-year follow-up. In our cohort n = 824 (9.8\%) ELGANs did not receive a timely first immunization with the hexavalent and pneumococcal vaccine. Risk factors for delayed vaccination were SGA status (18.1\% vs. 13.5\%; OR 1.3; 95\% CI: 1.1-1.7), impaired growth and surrogates for complicated clinical courses (i.e., need for inotropes, necrotizing enterocolitis). At 5 years of age, timely immunized children had a lower risk of bronchitis (episodes within last year: 27.3\% vs. 37.7\%; OR 0.60, 95\% CI: 0.42-0.86) but spirometry measures were unaffected. In conclusion, a significant proportion of ELGANs are untimely immunized, specifically those with increased vulnerability, even though they might particularly benefit from the immune-promoting effects of a timely vaccination.}, language = {en} } @article{RufThomasBrunneretal.2019, author = {Ruf, Katharina and Thomas, Wolfgang and Brunner, Maximilian and Speer, Christian P. and Hebestreit, Helge}, title = {Diverging effects of premature birth and bronchopulmonary dysplasia on exercise capacity and physical activity - a case control study}, series = {Respiratory Research}, volume = {20}, journal = {Respiratory Research}, doi = {10.1186/s12931-019-1238-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202449}, pages = {260}, year = {2019}, abstract = {Background Extreme prematurity has been associated with exercise intolerance and reduced physical activity. We hypothesized that children with bronchopulmonary dysplasia (BPD) would be especially affected based on long-term lung function impairments. Therefore, the objective of this study was to compare exercise capacity and habitual physical activity between children born very and extremely preterm with and without BPD and term-born children. Methods Twenty-two school-aged children (aged 8 to 12 years) born with a gestational age < 32 weeks and a birthweight < 1500 g (9 with moderate or severe BPD (=BPD), 13 without BPD (=No-BPD)) and 15 healthy term-born children (=CONTROL) were included in the study. Physical activity was measured by accelerometry, lung function by spirometry and exercise capacity by an incremental cardiopulmonary exercise test. Results Peak oxygen uptake was reduced in the BPD-group (83 ± 11\%predicted) compared to the No-BPD group (91 ± 8\%predicted) and the CONTROL group (94 ± 9\%predicted). In a general linear model, variance of peak oxygen uptake was significantly explained by BPD status and height but not by prematurity (p < 0.001). Compared to CONTROL, all children born preterm spent significantly more time in sedentary behaviour (BPD 478 ± 50 min, No-BPD 450 ± 52 min, CONTROL 398 ± 56 min, p < 0.05) and less time in moderate-to-vigorous-physical activity (BPD 13 ± 8 min, No-BPD 16 ± 8 min, CONTROL 33 ± 16 min, p < 0.001). Prematurity but not BPD contributed significantly to explained variance in a general linear model of sedentary behaviour and likewise moderate-to-vigorous-physical activity (p < 0.05 and p < 0.001 respectively). Conclusion In our cohort, BPD but not prematurity was associated with a reduced exercise capacity at school-age. However, prematurity regardless of BPD was related to less engagement in physical activity and more time spent in sedentary behaviour. Thus, our findings suggest diverging effects of prematurity and BPD on exercise capacity and physical activity."}, language = {en} } @article{HaarmannZimmermannBieberetal.2022, author = {Haarmann, Axel and Zimmermann, Lena and Bieber, Michael and Silwedel, Christine and Stoll, Guido and Schuhmann, Michael K.}, title = {Regulation and release of vasoactive endoglin by brain endothelium in response to hypoxia/reoxygenation in stroke}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {13}, issn = {1422-0067}, doi = {10.3390/ijms23137085}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284361}, year = {2022}, abstract = {In large vessel occlusion stroke, recanalization to restore cerebral perfusion is essential but not necessarily sufficient for a favorable outcome. Paradoxically, in some patients, reperfusion carries the risk of increased tissue damage and cerebral hemorrhage. Experimental and clinical data suggest that endothelial cells, representing the interface for detrimental platelet and leukocyte responses, likely play a crucial role in the phenomenon referred to as ischemia/reperfusion (I/R)-injury, but the mechanisms are unknown. We aimed to determine the role of endoglin in cerebral I/R-injury; endoglin is a membrane-bound protein abundantly expressed by endothelial cells that has previously been shown to be involved in the maintenance of vascular homeostasis. We investigated the expression of membranous endoglin (using Western blotting and RT-PCR) and the generation of soluble endoglin (using an enzyme-linked immunosorbent assay of cell culture supernatants) after hypoxia and subsequent reoxygenation in human non-immortalized brain endothelial cells. To validate these in vitro data, we additionally examined endoglin expression in an intraluminal monofilament model of permanent and transient middle cerebral artery occlusion in mice. Subsequently, the effects of recombinant human soluble endoglin were assessed by label-free impedance-based measurement of endothelial monolayer integrity (using the xCELLigence DP system) and immunocytochemistry. Endoglin expression is highly inducible by hypoxia in human brain endothelial monolayers in vitro, and subsequent reoxygenation induced its shedding. These findings were corroborated in mice during MCAO; an upregulation of endoglin was displayed in the infarcted hemispheres under occlusion, whereas endoglin expression was significantly diminished after transient MCAO, which is indicative of shedding. Of note is the finding that soluble endoglin induced an inflammatory phenotype in endothelial monolayers. The treatment of HBMEC with endoglin resulted in a decrease in transendothelial resistance and the downregulation of VE-cadherin. Our data establish a novel mechanism in which hypoxia triggers the initial endothelial upregulation of endoglin and subsequent reoxygenation triggers its release as a vasoactive mediator that, when rinsed into adjacent vascular beds after recanalization, can contribute to cerebral reperfusion injury.}, language = {en} }