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Handgretinger R.,University Hospital of Tuebingen
Current Opinion in Hematology | Year: 2012

Purpose of Review: In contrast to CD34+ positive selection, negative depletion strategies retain large numbers of effector cells in allogeneic peripheral stem cell grafts, such as natural killer (NK) and other cells. This review summarizes the clinical experience obtained using negative depletion approaches of CD3 and T-cell receptor (TcR)αβ T lymphocytes. Recent Findings: Attempts to improve immune reconstitution and to better exploit the graft-versus-malignancy effect after transplantation of T-cell-depleted grafts through the preservation of immune effector cells led to the development of CD3-, CD3/CD19-and more recently TcRαβ/CD19- negative depletion strategies of mobilized peripheral stem cell grafts. A faster immune reconstitution has been observed in patients with negatively depleted grafts after haploidentical transplantation, although no prospective randomized trials have been reported to date. In a randomized study of matched sibling and matched unrelated transplantation, CD3/CD19-depleted peripheral stem cell grafts led to a faster recovery of NK cells compared with the CD34+- positive selection group. Summary: New technologies allow the large-scale graft engineering of peripheral stem cells for clinical use in matched and mismatched stem cell transplantation. Further clinical trials are necessary to decide which of these methods is associated with a faster immune reconstitution and a better outcome after transplantation. © 2012 Wolters Kluwer Health | Lippincott Williams and Wilkins.


Mueller K.F.,University Hospital of Tuebingen
Systematic reviews | Year: 2013

Health professionals and policymakers aspire to make healthcare decisions based on the entire relevant research evidence. This, however, can rarely be achieved because a considerable amount of research findings are not published, especially in case of 'negative' results - a phenomenon widely recognized as publication bias. Different methods of detecting, quantifying and adjusting for publication bias in meta-analyses have been described in the literature, such as graphical approaches and formal statistical tests to detect publication bias, and statistical approaches to modify effect sizes to adjust a pooled estimate when the presence of publication bias is suspected. An up-to-date systematic review of the existing methods is lacking. The objectives of this systematic review are as follows:• To systematically review methodological articles which focus on non-publication of studies and to describe methods of detecting and/or quantifying and/or adjusting for publication bias in meta-analyses.• To appraise strengths and weaknesses of methods, the resources they require, and the conditions under which the method could be used, based on findings of included studies.We will systematically search Web of Science, Medline, and the Cochrane Library for methodological articles that describe at least one method of detecting and/or quantifying and/or adjusting for publication bias in meta-analyses. A dedicated data extraction form is developed and pilot-tested. Working in teams of two, we will independently extract relevant information from each eligible article. As this will be a qualitative systematic review, data reporting will involve a descriptive summary. Results are expected to be publicly available in mid 2013. This systematic review together with the results of other systematic reviews of the OPEN project (To Overcome Failure to Publish Negative Findings) will serve as a basis for the development of future policies and guidelines regarding the assessment and handling of publication bias in meta-analyses.


Handgretinger R.,University Hospital of Tuebingen
Blood | Year: 2014

In this issue of Blood, Wang et al suggest an algorithm for the selection of the best donor in HLA haplotype-mismatched transplantation of T-replete granulocyte colony-stimulating factor (G-CSF)-mobilized bone marrow and peripheral blood stem cells.1 © 2014 by The American Society of Hematology.


Oevermann L.,University Hospital of Tuebingen
Pediatric research | Year: 2012

Haploidentical transplantation in children opens the possibility to offer this treatment to every child with an otherwise incurable disease, such as some hematological or oncological malignancies, inborn or acquired bone marrow-failure syndromes, hemoglobinopathies, immunodeficiencies, or other genetic diseases. Although initial attempts at haploidentical transplantation were associated with a high transplant-related mortality, recent insights into the biology of haploidentical transplantation, the availability of effective in vivo large-scale graft-manipulation technology, and improved supportive care strategies have led to and are still leading to significantly better outcomes of haploidentical transplantation as compared with previous decades. In addition, expensive and time-consuming searches for matched unrelated donors (MUDs) as well as the expensive establishment and maintenance of cord blood banks are not necessary. Moreover, the worldwide donor registries comprise mainly donors of Caucasian origin and patients of non-Caucasian origin have a lower chance of finding a MUD. Therefore, haploidentical transplantation allows the treatment of children independently of their ethnic background in a timely fashion according to the status of their underlying disease.


Poets C.F.,University Hospital of Tuebingen
Sleep Medicine | Year: 2010

Apnea of prematurity (AOP) is a developmental sleep disorder which is yet to be completely understood. Although there is some evidence of brainstem immaturity, there is nothing to suggest that infants with AOP have gross deficits in respiratory control. It appears, however, that the early (and frequent) occurrence of hypoxemia during apnea in preterm infants is related to their low expiratory lung volume, which falls even further during apnea, while the accompanying bradycardia results from this combination of apnea and hypoxemia. Feeding is an important trigger for AOP. While hypoxemia during feeding is most likely related to an immature coordination between sucking, swallowing and breathing and potentially also to an immature laryngeal chemoreflex, hypoxemia after feeding may be caused by diaphragmatic fatigue; gastro-esophageal reflux only rarely plays a role. The time course of AOP, i.e., its increased occurrence during the second and third rather than the first week of life, together with data from physiological studies, also suggests a role for diaphragmatic fatigue. Additional factors include upper airway obstruction, persistence of the fetal response to hypoxia, i.e., ventilatory depression, and the close proximity between the eupneic and apneic CO2 thresholds in neonates. Observational data cannot provide definite answers on cause-and-effect issues but may provide a starting point for further studies into mechanisms involved in AOP and for the development of new therapeutic interventions. First, however, we need to better define how much AOP can be tolerated in an infant without endangering neurodevelopment. © 2010 Elsevier B.V.


Handgretinger R.,University Hospital of Tuebingen
Seminars in Oncology | Year: 2012

Haploidentical transplantation opens the possibility to offer this treatment to a large number of patients with an otherwise incurable disease, such as some hematologic or oncologic malignancies, inborn or acquired bone marrow failure syndromes, hemoglobinopathies, immunodeficiencies, or other genetic diseases. Initial attempts at haploidentical transplantation using unmanipulated bone marrow were associated with a high transplant-related mortality. However, recent insights into the biology of haploidentical transplantation, the availability of effective in vivo large-scale graft-manipulation technology, and improved supportive care strategies have led to and are still leading to significantly better outcomes compared to previous decades. Methods for the in vitro depletion of T lymphocytes from mobilized peripheral blood stem cells (PBSC) to prevent graft-versus-host disease (GvHD) have facilitated the wider use and acceptance of haploidentical transplantation in children and adult patients. Besides in vitro T-cell depletion techniques, other methods, such as the isolation of alloreactive natural killer (NK) cells, virus-specific T lymphocytes, and other effector or regulatory cells are nowadays available to rapidly rebuild the immune system after haploidentical transplantation for the prevention of severe infections or relapses of the underlying diseases. © 2012 Elsevier Inc. All rights reserved.


Kuemmerle-Deschner J.B.,University Hospital of Tuebingen
Seminars in Immunopathology | Year: 2015

The cryopyrin-associated periodic syndrome (CAPS) is a severity spectrum of rare diseases. CAPS comprises the three conditions previously described as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disorder (NOMID), also known as chronic infantile neurologic, cutaneous, and articular (CINCA) syndrome. The clinical phenotype of CAPS is characterized by systemic inflammation. General symptoms are fatigue and fever. Local manifestations affect multiple tissues such as skin, joints, muscles, eyes, and the central nervous system. Distinct clinical features are characteristic for each subphenotype. In FCAS, these are cold-induced urticaria and fever, inMWS systemic amyloidosis and hearing loss and in NOMID/CINCA central nervous system inflammation and bone deformities. CAPS is caused by single heterozygous germline or somatic gain of function mutations in the NLRP3 gene encoding the protein cryopyrin. Cryopyrin nucleates an NLRP3 inflammasome, which regulates the activation and cleavage of caspase-1 that cleaves the pro-inflammatory cytokines, IL-1β and IL-18. IL-1β plays the key role in the induction of inflammation in CAPS. This has been confirmed by the application of IL-1 blocking agents, which lead not only to a rapid and sustained reversal of daily symptoms but also to some extent of long-term disease sequelae. To prevent CAPS-induced organ damage, early diagnosis and swift initiation of effective treatment are mandatory. ©Springer-Verlag Berlin Heidelberg 2015.


Rupp F.,University Hospital of Tuebingen
The International journal of oral & maxillofacial implants | Year: 2011

Hydrophilicity is gaining increasing interest as a factor that might influence the osseointegration of dental implants. Therefore, in this study the dynamic wetting behavior of currently marketed dental titanium implants was analyzed by tensiometry, and its relationship to surface topography was examined. Nine screw-type implant systems from eight manufacturers were evaluated. Dynamic water contact angles were analyzed by tensiometric multiloop Wilhelmy experiments (10 loops, 10 mm/min immersion speed). The wetted length (perimeter) of the immersed samples was estimated by three-dimensional picture profile measurement of the thread height of the respective implant screws. Wettability was quantified by first advancing contact angles. Additionally, static contact angles were determined using the sessile drop technique. All implant surfaces were characterized by scanning electron microscopy (SEM). Contact angle data were subjected to one-way analysis of variance followed by the Student t test. SEM revealed different types of surface morphology resulting from the different manufacturing processes. The first advancing mean contact angles of all implants ranged from 0 degrees (SLActive) to 138 degrees (OsseoSpeed), demonstrating statistically significant differences between implants. Because of kinetic hysteresis, initially hydrophobic implants became hydrophilic during following immersion loops. The tensiometric method was used to compare wettability of dental implants. A range from fully wettable/superhydrophilic to virtually unwettable/hydrophobic was observed on the implant surfaces examined.


Most available postmenopausal hormone replacement therapies (HRT) offer similar efficacy, but differ with respect to the cardiovascular risks associated with their use. There is a wealth of evidence to suggest that, unlike oral estrogens, transdermal estradiol does not increase the risk of venous thromboembolism, probably due to its lack of effect on the coagulation cascade, including thrombin generation and resistance to activated protein C, and does not increase the risk of stroke. It is cardioprotective, significantly reducing the incidence of myocardial infarction compared with non-users; it significantly reduces the incidence of new-onset diabetes, a risk factor for myocardial infarction. Micronized progesterone has also been shown not to increase the risk of venous thromboembolism and further reduced the incidence of new-onset diabetes when combined with transdermal estrogen. Micronized progesterone has a neutral effect on the vasculature, including a neutral or beneficial effect on blood pressure. Therefore, experimental and clinical data indicate that transdermal estradiol and micronized progesterone could represent the optimal HRT, particularly in women at risk of adverse events. © 2012 International Menopause Society.


Patent
University Hospital of Tuebingen | Date: 2012-03-09

The present invention relates to a method for diagnosing and/or predicting the development of neurodegenerative diseases; in the method, white blood cells are isolated and enriched or cultivated for forming colony-forming units, wherein CFU-M and other CFU are formed. Subsequently, the relative number of CFU-M formed in the previous cultivation(/enrichment step relative to the other CFUs formed are determined.

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