Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta Lineage Thymocytes

Notch proteins influence cell fate decisions in many developmental systems. During lymphoid development, Notch1 signaling is essential to direct a bipotent T/B precursor toward the T cell fate, but the role of Notch1 at later stages of T cell development remains controversial. We have recently reported that tissue-specific inactivation of Notch1 in immature (CD44(-) CD25(+)) thymocytes does not affect subsequent T cell development. Here, we demonstrate that loss of Notch1 signaling at an earlier (CD44(+)CD25(+)) developmental stage results in severe perturbation of alpha beta but not gamma delta lineage development. Immature Notch1(-/-) thymocytes show impaired VDJ beta rearrangement and aberrant pre-TCR-independent survival. Collectively, our data demonstrate that Notch1 controls several nonredundant functions necessary for alpha beta lineage development.     

Die Rolle des Erythropoietinmangels in der Pathogenese der renalen Anämie

Zusammenfassung Es wird eine Übersicht gegeben über klinische Untersuchungen, die mit einem hochsensiblen in-vitro Erythropoietin Assay (foetale Mäuseleberzellkultur) zur Klärung der umstrittenen Rolle des Erythropoietinmangels in der Pathogenese der renalen Anämie an großen Patientenpopulationen durchgeführt wurden. Die Studien betrafen: a.) chronisch Nierenkranke mit variierender Funktionsein-schränkung in der Vordialysephase b.) nicht nephrektomierte und anephrische chronische Dialysepatienten.Die bisher vorliegenden Ergebnisse belegen, daß die Anfangsphase der renalen Anämie mit einem kompensatorischen Anstieg der Serumerythropoietinkonzentration einhergeht und somit ein Erythropoietinmangel nicht die primäre Ursache dieser Anämie sein kann; lediglich ein relativer Erythropoietinmangel ist anzunehmen. Erst in der Terminalphase der Niereninsuffizienz wird der Erythropoietinmangel absolut, so bei 50% der untersuchten chronischen, nichtnephrektomierten Hämodialysepatienten und bei allen anephrischen Patienten. An einzelnen Patienten läßt sich aber selbst in der terminalen Niereninsuffizienz eine Regulierbarkeit der Serumerythropoietinkonzentration über den Hämatokrit im Sinne eines negativen feedback nachweisen, der auf einem subnormalen Hämatokritniveau arbeitet.     

Damaged chromatin does not prevent the exit from metaphase I in fused mouse oocytes

The presence of checkpoint mechanisms which are able to recognize damaged chromatin and thereafter to prevent exit from metaphase I has been investigated in giant mouse oocytes produced by fusion of a normal metaphase I oocyte with an equivalent oocyte with damaged chromatin. The presence of damaged chromatin did not prevent the onset of anaphase I in both sets of chromatin in the fused cells. Interestingly, fused or unfused cells containing only damaged chromatin failed to enter anaphase and persisted instead in a metaphase-like state. These results demonstrate the fragility of checkpoint controls in mammalian female germ cells.      

Venous drainage patterns in a case of pseudotumor cerebri following unilateral radical neck dissection

We report the extracranial venous ultrasound findings in a case of pseudotumor cerebri (PTC) following unilateral radical neck dissection (rND). PTC is known to be a rare complication following bilateral rND, and is caused by venous outflow obstruction. Single cases of PTC have been reported after unilateral rND, and are thought to be due to resection of the dominant internal jugular vein (IJV) in the presence of a hypoplastic or aplastic contralateral transverse sinus. Our patient developed PTC despite prominent flow in the contralateral IJV as shown by venous ultrasound. No compensatory increase in flow in the vertebral veins was observed, as confirmed by digital subtraction angiography. We conclude that the physiological collateral function of the vertebral venous system and deep neck veins was insufficient and contributed to global venous outflow obstruction in our case of unilateral rND.     

Impact of HLA-compatibilities in patients undergoing liver transplantation for HBV-cirrhosis

Liver transplantation (OLT) for end-stage chronic hepatitis-B-virus (HBV) infection is frequently complicated by HBV recurrence. In the present study we investigated whether human leucocyte antigen (HLA)-matching influences the outcome after OLT. In a retrospective analysis we reviewed 84 recipients of liver transplants for end-stage HBV-cirrhosis and complete HLA-typing for outcome after OLT. Follow-up ranges from 1 to 110 months (median = 55.6 months). Immunosuppression consisted of Cyclosporin A (CsA)-based quadruple induction therapy or Tacrolimus-based induction protocols. Immunoprophylaxis with hepatitis B immunoglobulin was started at OLT and continued long-term. Actuarial 1- and 5-yr graft survival figures were 90.5 and 80.4%, respectively. Hepatitis-B recurrence was responsible for 15 of 20 (75%) graft failures. We observed a significantly improved graft survival in patients with more HLA-A, -B compatibilities (p = 0.02), whereas the degree of HLA-DR compatibilities did not influence the outcome. The occurrence of HBV-reinfection was significantly lower in HLA-A, -B matched grafts (p < 0.05). Additionally, graft survival was prolonged in patients with HBV-reinfection and 1 or 2 HLA-B compatibilities when compared with patients with HBV-reinfection and a complete HLA-B mismatch (p = 0.02). In conclusion, this retrospective analysis shows that more HLA-A, -B compatibilities seems to be associated with an improved graft survival in patients after OLT for end-stage HBV infection.     

Stammzellen aus dem Fettgewebe

While stem cells derived from the bone marrow are well-known in clinical medicine, fatty tissue as a source of mesenchymal stem cells is still the subject of recent research. However, adipose-derived stem cells (ASC) are not only harvested less invasively, i.e. via minimally invasive liposuction, but also yield higher numbers of multipotent stem cells. Due to cell-cell interactions and also because of the very favorable secretion profile of growth factors and cytokines ASCs displayed an extraordinary regenerative potential in recent preclinical and clinical applications and achieved a significantly better healing in ischemic muscle, heart, and brain insults and in impaired wound healing. ASCs enhanced regeneration in skeletal tissues such as cartilage or bone. They also revealed immunomodulatory effects and improved the clinical status in immunological diseases. In conclusion ASCs are comparable to bone marrow-derived stem cells concerning possible applications in clinical medicine.