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Immunological reconstitution and infections after alloHCT - a comparison between post-transplantation cyclophosphamide, ATLG and non-ATLG based GvHD prophylaxis
No full textImmunological reconstitution after allogeneic hematopoietic cell transplantation (alloHCT) is critical for patient survival. We compared short- and long-term immune reconstitution and clinical endpoints in adult recipients of haploidentical or mismatched T cell replete peripheral blood stem cell transplants (PBSCT) with post-transplant cyclophosphamide as GvHD prophylaxis (PTCY, n = 68) to: (a) patients receiving matched unrelated grafts and anti-T lymphocyte globulin (ATLG) (MUD/ATLG, n = 280); (b) patients with a mismatched donor and ATLG (MM/ATLG, n = 54); and (c) recipients of matched related grafts without ATLG (MRD/NoATLG, n = 97). PTCY was associated with delayed neutrophil engraftment, low NK-cell counts on day 30 and reduced CD8+ cells on days 60–80. In terms of long-term reconstitution, PTCY recipients demonstrated significantly higher CD4+ counts from day 100–365, primarily derived from naïve T cells. Additionally, B-lymphocyte counts at one year were highest in the PTCY group. Early morbidity and mortality due to infectious complications (viral reactivation, (blood stream) infections) were most frequent in PTCY patients during the first three months. However, beyond three months, no PTCY patient suffered a fatal infection. Our study highlights the pattern of early immunodeficiency followed by robust long-term immune reconstitution in PTCY recipients, identifying critical time periods of risk that could be targeted to optimise patient survival and reduce infectious complications
Identification of phosphatases that dephosphorylate the co-chaperone BAG3
No full textThe co-chaperone BAG3 plays critical roles in maintaining cellular proteostasis. It associates with 14-3-3 proteins during the trafficking of aggregation-prone proteins and facilitates their degradation through chaperone-assisted selective autophagy in cooperation with small heat shock proteins. Although reversible phosphorylation regulates BAG3 function, the involved phosphatases remain unknown. Here, we used affinity purification mass spectrometry to identify phosphatases that target BAG3. Of the hits, we evaluated the involvement of protein phosphatase-1 (PP1) using chemical inhibitors and activators in in vitro and cellular approaches. Our results demonstrate that PP1 can dephosphorylate BAG3-pS136 in cells and counteract 14-3-3γ association with BAG3 at this motif. Furthermore, protein phosphatase-5 (PP5) co-enriched with proteostasis-related proteins, and it has the capacity to dephosphorylate a BAG3 phosphorylation-site cluster regulating the interaction of BAG3 with small heat shock proteins and BAG3-mediated protein degradation. Our findings provide new insights into the regulation of BAG3 by phosphatases. This paves the way for future research focused on the precise control of BAG3 function through its regulatory proteins, potentially holding therapeutic promise for diseases characterized by disrupted proteostasis
First experience using a new minimally invasive screw-rod system for completely percutaneous pedicle screw fixation of the cervical spine
No full textDelirium after cardiac arrest: incidence, risk factors, and association with neurologic outcome - insights from the Freiburg Delirium Registry
No full textStability of the Wulff shape with respect to anisotropic curvature functionals
No full textFor a function f which foliates a one-sided neighborhood of a closed hypersurface M, we give an estimate of the distance of M to a Wulff shape in terms of the -norm of the traceless F-Hessian of f, where F is the support function of the Wulff shape. This theorem is applied to prove quantitative stability results for the anisotropic Heintze-Karcher inequality, the anisotropic Alexandrov problem, as well as for the anisotropic overdetermined boundary value problem of Serrin-type
An advancing solution for narrow aortic pathologies in thoracoabdominal endovascular repair
No full textSafety and efficiency of trainees performing bilateral internal thoracic artery coronary bypass grafting using the T-graft technique
No full textCrohn’s disease, irritable bowel syndrome, and chronic fatigue: the importance of communication and symptom management - a case report
No full textBackgroundCrohn’s disease and irritable bowel syndrome may both cause abdominal pain and diarrhea. Irritable bowel syndrome not only is an important differential diagnosis for Crohn’s disease but also occurs in one out of three patients with Crohn’s disease in remission in parallel. If not adequately diagnosed and treated, additional functional symptoms such as fatigue and/or muscle pain may develop, indicating a more severe course.Case presentationA 64-year-old Caucasian male with long-standing, widely inactive Crohn’s disease presented with persistent diarrhea, bloating, abdominal pain, general fatigue, unexplained hip pain, and frequent shivering with cold extremities, which had worsened following a gastrointestinal infection and psychological stress. A plausible explanation of his symptoms, based on an understanding of mind–body interactions, the autonomic nervous system, and temperature regulation, combined with symptom relief, was associated with rapid and sustainable improvement. After 2.5 years of follow-up, the patient is almost symptom-free.ConclusionsThis case report exemplifies the interrelation between organic (Crohn’s disease) and functional diseases (irritable bowel syndrome, chronic fatigue syndrome, and somatoform pain). It further demonstrates that these connections may be overlooked in daily practice and that providing a plausible explanation in combination with symptom relief may be important for patients with functional syndromes
A conformational change of C-reactive protein drives neutrophil extracellular trap formation in inflammation
No full textBackgroundC-reactive protein (CRP) represents a routine diagnostic marker of inflammation. Dissociation of native pentameric CRP (pCRP) into the monomeric structure (mCRP) liberates proinflammatory features, presumably contributing to excessive immune cell activation via unknown molecular mechanisms.ResultsIn a multi-translational study of systemic inflammation, we found a time- and inflammation-dependent pCRP dissociation into mCRP. We were able to confirm that mCRP co-localizes with leukocytes at the site of injury after polytrauma and therefore assessed whether the CRP conformation potentiates neutrophil activation. We found mCRP-induced neutrophil-extracellular trap formation in vitro and ex vivo involving nicotinamide adenine dinucleotide phosphate oxidase activation, p38/mitogen-activated protein kinase signaling, and histone H3 citrullination. Mimicking the trauma milieu in a human ex vivo whole blood model, we found significant mCRP generation as well as NET formation, prevented by blocking pCRP conformational changes.ConclusionsOur data provide novel molecular insights how CRP dissociation contributes to neutrophil activation as driver of various inflammatory disorders
