Refine
Document Type
- Article (11)
Has Fulltext
- yes (11)
Is part of the Bibliography
- no (11)
Keywords
- AB-serum (1)
- Antifungal agents (1)
- Aspergillosis (1)
- CIK cells (1)
- COVID-19 (1)
- CVID (1)
- Completed suicide (1)
- European Society for Immunodeficiencies (ESID) (1)
- FDG-PET/CT (1)
- German PID-NET registry (1)
Institute
- Medizin (6)
- Biochemie und Chemie (3)
- Extern (1)
- Pharmazie (1)
Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs.
Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel.
Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy.
Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.
In evidence-based weight-loss programs weight regain is common after an initial weight reduction. Eating slowly significantly lowers meal energy intake and hunger ratings. Despite this knowledge, obese individuals do not implement this behaviour. We, thus tested the hypothesis of changing eating behaviour with an intra-oral medical device leading to constant weight reduction in overweight and obesity.
Six obese patients (6 men, age 56 ± 14, BMI 29 ± 2 kg / m2) with increased CVRF profile were included in this prospective study. All patients had been treated for obesity during the last 10 years in a single centre and had at least 3 frustrate evidence-based diets. Patients received a novel non-invasive intra-oral medical device to slow eating time. Further advice included not to count calories, to avoid any other form of diet, to take their time with their meals, and to eat whatever they liked.
This device was used only during meals for the first 4 to 8 weeks for a total of 88 [20–160] hours. Follow-up period was 23 [15–38] months. During this period, patients lost 11% [5–20%] (p<0.001) of their initial weight. At 12 months, all patients had lost >5%, and 67% (4/6) achieved a >10% bodyweight loss. In the course of the study, altered eating patterns were observed. There were no complications with the medical device. Of note, all patients continued to lose weight after the initial intervention period (p<0.001) and none of them had weight regain.
With this medical device, overweight and obese patients with a history of previously frustrating attempts to lose weight achieved a significant and sustained weight loss over two years. These results warrant the ongoing prospective randomised controlled trial to prove concept and mechanism of action.
Background: Nitric oxide (NO) is an essential vasodilator. In vascular diseases, oxidative stress attenuates NO signaling by both chemical scavenging of free NO and oxidation and down-regulation of its major intracellular receptor, the alpha/beta heterodimeric heme-containing soluble guanylate cyclase (sGC). Oxidation can also induce loss of sGC's heme and responsiveness to NO.
Results: sGC activators such as BAY 58-2667 bind to oxidized/heme-free sGC and reactivate the enzyme to exert disease-specific vasodilation. Here we show that oxidation-induced down-regulation of sGC protein extends to isolated blood vessels. Mechanistically, degradation was triggered through sGC ubiquitination and proteasomal degradation. The heme-binding site ligand, BAY 58-2667, prevented sGC ubiquitination and stabilized both alpha and beta subunits.
Conclusion: Collectively, our data establish oxidation-ubiquitination of sGC as a modulator of NO/cGMP signaling and point to a new mechanism of action for sGC activating vasodilators by stabilizing their receptor, oxidized/heme-free sGC.
Oxidative stress attenuates the NO-cGMP pathway, e.g. in the vascular system, through scavenging of free NO radicals by superoxide O2•-, by inactivation of soluble guanylyl cyclase (sGC) via oxidation of its central Fe2+ ion, and by down-regulation of sGC protein levels. While the former pathways are well established, the molecular mechanisms underlying the latter are still obscure. Using oxidative sGC inhibitor ODQ we demonstrate rapid down-regulation of sGC protein in mammalian cells. Co-incubation with proteasomal inhibitor MG132 results in accumulation of ubiquitinated sGC whereas sGC activator BAY 58–2667 prevents ubiquitination. ODQ-induced down-regulation of sGC is mediated through selective ubiquitination of its b subunit, and BAY 58–2667 abrogates this effect. Ubiquitination of sGC-b is dramatically enhanced by E3 ligase CHIP. Our data indicate that oxidative stress promotes ubiquitination of sGC b subunit through E3 ligase CHIP, and that sGC activator 58–2667 reverts this effect, most likely through stabilization of the heme-free b subunit. Thus the deleterious effects of oxidative stress can be counter-balanced by an activator of a key enzyme of vascular homeostasis.
In Sachsen-Anhalt stellen eine Vielzahl von Vorhabensplanungen bundesweiter, landesweiter und lokaler Bedeutung qualitativ und quantitativ neue Ansprüche an die Land- und Raumnutzung. Dabei ist die Auseinandersetzung mit den Vorhabensfolgen, insbesondere den verursachten Veränderungen der Umwelt für alle Vorhabensträger gesetzlich zwingend vorgeschrieben. Erklärtes Ziel ist es, weiterem unnötigen Verbrauch wertvoller Umwelt und damit einer Verschlechterung der Umweltsituation schon auf der Ebene der Planung wirksam vorzubeugen.
The promotion and extension of continuous cover mixed stands with a simultaneous reduction of conifer-monocultures play a major role in current silvicultural practices in Central Europe. It is assumed that the admixture of the natural dominant beech (Fagus sylvatica) in pure non site-specific conifer stands automatically indicates better conditions in terms of nature conservation and forest management. To test this hypothesis three different conifer-beech-comparisons of pure and mixed stands in Lower Saxony are studied, analyzing plant species diversity and naturalness of understory vegetation as one important indicator for the ecological status of forests. Each comparison includes pure coniferous stands (Picea abies, Pinus sylvestris, Pseudotsuga menziesii), mixed coniferous-beech-stands, and pure beech stands on similar acidic mineral soils where the potential natural vegetation will be an oligotrophic beech forest (L u z u l o - Fa g e t um). The age of stands varies between 50 and 150 years. To specify tree species influence on site conditions and vegetation, the study also includes light climate and soil data of the stands. It is observed that, with regard to all comparisons, the admixture of beech reduces plant species diversity but increases naturalness of the stands. The intensity of beech admixture effects differs. While in Scots pine stands the impact of admixed beech is very noticeable, with the mixed stands being nearly identical with pure beech stands, the species change in Douglas-fir and Norway spruce stands proceeds more slowly. Assuming that the status in nature conservation and forest management is improving with increasing plant species diversity and increasing naturalness, the results of this study show a contrary development on a stand scale, as the potential natural vegetation of the L u z u l o - F a g e t u m is in its self very species poor on vascular plants.
The Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Oncology (DGHO) here presents its updated recommendations for the treatment of documented fungal infections. Invasive fungal infections are a main cause of morbidity and mortality in cancer patients undergoing intensive chemotherapy regimens. In recent years, new antifungal agents have been licensed, and agents already approved have been studied in new indications. The choice of the most appropriate antifungal treatment depends on the fungal species suspected or identified, the patient’s risk factors (e.g., length and depth of neutropenia), and the expected side effects. This guideline reviews the clinical studies that served as a basis for the following recommendations. All recommendations including the levels of evidence are summarized in tables to give the reader rapid access to the information.
Cytokine-induced killer (CIK) cells are an immunotherapeutic approach to combat relapse following allogeneic hematopoietic stem cell transplantation (HSCT) in acute leukemia or myelodysplastic syndrome (MDS) patients. Prompt and sequential administration of escalating cell doses improves the efficacy of CIK cell therapy without exacerbating graft vs. host disease (GVHD). This study addresses manufacturing-related issues and aimed to develop a time-, personal- and cost-saving good manufacturing process (GMP)-compliant protocol for the generation of ready-for-use therapeutic CIK cell doses starting from one unstimulated donor-derived peripheral blood (PB) or leukocytapheresis (LP) products. Culture medium with or without the addition of either AB serum, fresh frozen plasma (FFP) or platelet lysate (PL) was used for culture. Fresh and cryopreserved CIK cells were compared regarding expansion rate, viability, phenotype, and ability to inhibit leukemia growth. Cell numbers increased by a median factor of 10-fold in the presence of FFP, PL, or AB serum, whereas cultivation in FFP/PL-free or AB serum-free medium failed to promote adequate CIK cell proliferation (p < 0.01) needed to provide clinical doses of 1 × 106 T cells/kG, 5 × 106 T cells/kG, 1 × 107 T cells/kG, and 1 × 108 T cells/kG recipient body weight. CIK cells consisting of T cells, T- natural killer (T-NK) cells and a minor fraction of NK cells were not significantly modified by different medium supplements. Moreover, neither cytotoxic potential against leukemic THP-1 cells nor cell activation shown by CD25 expression were significantly influenced. Moreover, overnight and long-term cryopreservation had no significant effect on the composition of CIK cells, their phenotype or cytotoxic potential. A viability of almost 93% (range: 89–96) and 89.3% (range: 84–94) was obtained after freeze-thawing procedure and long-term storage, respectively, whereas viability was 96% (range: 90-97) in fresh CIK cells. Altogether, GMP-complaint CIK cell generation from an unstimulated donor-derived PB or LP products was feasible. Introducing FFP, which is easily accessible, into CIK cell cultures was time- and cost-saving without loss of viability and potency in a 10-12 day batch culture. The feasibility of cryopreservation enabled storage and delivery of sequential highly effective ready-for-use CIK cell doses and therefore reduced the number of manufacturing cycles.
Many interesting and important membrane proteins are hetero-oligomeric. However, besides naturally abundant examples, the structures of relatively few such complexes are known. Partly, this is due to difficulties in expression, stoichiometric assembly, and in the evaluation of their stability prior to crystallization trials. Here we describe a new approach, which allows rapid assessment of protein complex quality, assembly and stoichiometry, simplifying the search for conditions conducive to long-term stability and crystallization. Multicolour fluorescence size-exclusion chromatography (MC-FSEC) is used to enable tracking of individual subunits through expression, solubilization and purification steps. We show how the method has been applied to the heterodimeric transporter associated with antigen processing (TAP) and demonstrate how it may be extended in order to analyse membrane multisubunit assemblies.
The consequences of the current COVID-19 pandemic for mental health remain unclear, especially regarding the effects on suicidal behaviors. To assess changes in the pattern of suicide attempt (SA) admissions and completed suicides (CS) in association with the COVID-19 pandemic. As part of a longitudinal study, SA admissions and CS are systematically documented and analyzed in all psychiatric hospitals in Frankfurt/Main (765.000 inhabitants). Number, sociodemographic factors, diagnoses and methods of SA and CS were compared between the periods of March–December 2019 and March–December 2020. The number of CS did not change, while the number of SA significantly decreased. Age, sex, occupational status, and psychiatric diagnoses did not change in SA, whereas the percentage of patients living alone while attempting suicide increased. The rate and number of intoxications as a SA method increased and more people attempted suicide in their own home, which was not observed in CS. Such a shift from public places to home is supported by the weekday of SA, as the rate of SA on weekends was significantly lower during the pandemic, likely because of lockdown measures. Only admissions to psychiatric hospitals were recorded, but not to other institutions. As it seems unlikely that the number of SA decreased while the number of CS remained unchanged, it is conceivable that the number of unreported SA cases increased during the pandemic. Our data suggest that a higher number of SA remained unnoticed during the pandemic because of their location and the use of methods associated with lower lethality.