New technique of orthotopic en bloc transplantation of the porcine liver and duct-ligated pancreas.

A new technique of transplanting porcine liver and pancreas en bloc in an orthotopic position is described. The pancreatic duct was ligated. Recipients were made diabetic either by total pancreatectomy or by intravenous administration of streptozotocin, (100 mg/kg body wt). Careful correction of electrolyte and fluid disturbances in recipient animals was mandatory before and after surgery. No rejection of either liver or pancreas grafts was seen. The endocrine function of the pancreatic grafts was adequate.     

Ein Verfahren zur Bestimmung des relativen Wassergehaltes des Stratum corneum der menschlichen Haut

Zusammenfassung Es wird eine Methode zur Messung der relativen Hautfeuchtigkeit (=Feuchtigkeit des Stratum corneum) beschrieben.Grundlage des Verfahrens ist die Bestimmung der Gleichstromleitfähigkeit der Haut bei einem Differenzpotential von 3 V. Wegen der Inhomogenität der Durchfeuchtung der Hornschict, die sich aus der Natur der Haut als Grenzorgan gegenüber den unterschiedlichsten Feuchtigkeiten der anorganischen Umwelt ergibt, läßt sich nur eine mittlere Hautfeuchtigkeit messen.Die Korrelation der Gleichstromleitfähigkeit mit der relativen Feuchtigkeit wird deshalb durch die Eigenschaften eines homogenen, gravimetrisch analysierbaren Modells definiert. Das Verfahren wurde zur Untersuchung der Zeitabhängigkeit der relativen Feuchtigkeit nach Einwirkung eines Wasserbades angewandt. Es zeigte sich, daß die Hautfeuchtigkeit nach Anwendung eines Bades einen Gleichgewichtszustand anstrebt, der unter der ursprünglichen Hautfeuchtigkeit liegt. Die Abklingkinetik der Feuchtigkeit war hierbei nach einer schnellen Anfangsphase einfach exponentiell. Dies wird als Beweis für die Anwendbarkeit der Beziehung zwischen relativer Feuchtigkeit und Gleichspannungsleitfähigkeit des Modells zur Ermittlung der relativen Feuchtigkeit der Hornschicht gewertet.D82 (Diss. TH Aachen)     

ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling

Approximately 25% of childhood acute lymphoblastic leukemias carry the ETV6/RUNX1 fusion gene. Despite their excellent initial treatment response, up to 20% of patients relapse. To gain insight into the relapse mechanisms, we analyzed single nucleotide polymorphism arrays for DNA copy number aberrations (CNAs) in 18 matched diagnosis and relapse leukemias. CNAs were more abundant at relapse than at diagnosis (mean 12.5 vs 7.5 per case; P=.01) with 5.3 shared on average. Their patterns revealed a direct clonal relationship with exclusively new aberrations at relapse in only 21.4%, whereas 78.6% shared a common ancestor and subsequently acquired distinct CNA. Moreover, we identified recurrent, mainly nonoverlapping deletions associated with glucocorticoid-mediated apoptosis targeting the Bcl2 modifying factor (BMF) (n=3), glucocorticoid receptor NR3C1 (n=4), and components of the mismatch repair pathways (n=3). Fluorescence in situ hybridization screening of additional 24 relapsed and 72 nonrelapsed ETV6/RUNX1-positive cases demonstrated that BMF deletions were significantly more common in relapse cases (16.6% vs 2.8%; P=.02). Unlike BMF deletions, which were always already present at diagnosis, NR3C1 and mismatch repair aberrations prevailed at relapse. They were all associated with leukemias, which poorly responded to treatment. These findings implicate glucocorticoid-associated drug resistance in ETV6/RUNX1-positive relapse pathogenesis and therefore might help to guide future therapies.     

Nonorganic hearing loss

Nonorganic hearing loss is a decrease in hearing that is unexplained by anatomic or physiologic abnormalities, or both. The term is synonymous with functional hearing loss and pseudohypacusis. The demographics and potential etiologies of nonorganic hearing loss are described. History and physical findings that indicate a functional hearing loss are also discussed. A review of the anatomy and physiology of the auditory system is provided as a background for the discussed objective tests of hearing thresholds. Finally, conditions that may mimic functional hearing loss are described in detail.     

Genomic Biomarkers for a Binary Clinical Outcome in Early Drug Development Microarray Experiments

In this article, we discuss methods to select three different types of genes (treatment related, response related, or both) and investigate whether they can serve as biomarkers for a binary outcome variable. We consider an extension of the joint model introduced by Lin et al. (2010 Lin , D. , Shkedy , Z. , Molenberghs , G. , Goehlmann , H. , Talloen , W. , Bijnens , L. ( 2010 ). Selection and evaluation of gene-specific biomarkers in pre-clinical and clinical microarray experiments . Online Journal of Bioinformatics 11 ( 1 ): 106 – 127 . [Google Scholar]) and Tilahun et al. (2010 Tilahun , A. , Lin , D. , Shkedy , Z. , Geys , H. , Alonso , A. , Peeters , P. , Talloen , W. , Drinkenburg , W. , Göhlmann , H. , Gorden , E. , Bijnens , L. , Molenberghs , G. ( 2010 ). Genomic biomarkers for depression: Feature-specific and joint biomarkers . Statistics in Biopharmaceutical Research 2 ( 3 ): 419 – 434 .[Taylor &; Francis Online], [Web of Science ®] , [Google Scholar]) for a continuous response. As the model has certain drawbacks in a binary setting, we also present a way to use classical selection methods to identify subgroups of genes, which are treatment and/or response related. We evaluate their potential to serve as biomarkers by applying DLDA to predict the response level.     

Starvation and emotion regulation in anorexia nervosa

Self-starvation, with concomitant weight loss, may serve as a dysfunctional behavior to attenuate negative affective states in anorexia nervosa (AN). A total of 91 participants composed of patients with acute AN, women recovered from AN, clinical controls with either depression or anxiety disorder, and healthy controls were tested on a measure of emotion regulation. Patients with acute AN as well as recovered patients with AN and clinical controls showed increased emotion regulation difficulties as compared with healthy controls. In patients with acute AN, a specific association between body weight and emotion regulation was found: the lower the body mass index in patients with acute AN, the lesser were their difficulties in emotion regulation. This association could only be found in the subsample of patients with acute AN but not in the control groups. Moreover, there were no confounding effects of depression or duration of illness. The findings are consistent with the hypothesis that self-starvation with accompanying low body weight serves as a dysfunctional behavior to regulate aversive emotions in AN.     

Deposition of complement C3c, immunoglobulin (Ig)G4 and IgG at the basement membrane of pancreatic ducts and acini in autoimmune pancreatitis

Detlefsen S, Bräsen J H, Zamboni G, Capelli P & Klöppel G
(2010) Histopathology 57, 825–835 Deposition of complement C3c, immunoglobulin (Ig)G4 and IgG at the basement membrane of pancreatic ducts and acini in autoimmune pancreatitis Aims: Autoimmune pancreatitis (AIP) is a type of pancreatitis whose immunopathogenesis is still unknown. It has been reported that renal biopsy specimens from patients diagnosed with both AIP and tubulointerstitial nephritis reveal deposits containing complement C3, immunoglobulin (Ig)G and IgG4 at the tubular basement membranes (BMs). The aim was to investigate the deposition of complement and immunoglobulins in pancreatic tissue from AIP patients compared to non‐AIP patients. Methods: Double immunofluorescence microscopy for C3c, IgG4 and IgG together with CK7, trypsin, collagen IV, CD31 and CD79a, as well as immunofluorescence microscopy for C1q, IgA and IgM, were performed on frozen pancreatic tissue from AIP and alcoholic chronic pancreatitis (ACP) patients. Results: In AIP patients, complement C3c, IgG4 and IgG were deposited at the collagen IV‐positive BMs of pancreatic and bile ducts and of acini. In a minority of the ACP patients, weak C3c‐positive BM deposits were detected, but no IgG4‐ or IgG‐positive BM deposits were present. Conclusion: The deposition of C3c, IgG4 and IgG at the BM of small‐ and medium‐sized ducts and acini of the pancreas is characteristic of AIP. This suggests that immune complex‐mediated destruction of ducts and acini play a role in the pathogenesis of AIP.     

CD4(+)CD7(-) T cells compose the dominant T-cell clone in the peripheral blood of patients with Sézary syndrome

BACKGROUND: Absence of CD7 antigen expression in T cells defines a subset of normal CD4(+) CD45RO(+) CD45RA(-) memory cells and is furthermore observed in Sézary syndrome (SS). OBJECTIVE: Our purpose was to identify circulating T-cell clones in patients with SS and to elucidate whether the dominant T-cell clones express the CD7 antigen. METHODS: Peripheral blood lymphocytes of patients with SS were analyzed by two-color flow cytometry using antibodies to the V beta region of the T cell receptor (TCR) in combination with an antibody to CD7. In addition, T cells were analyzed for TCR-gamma gene rearrangement by polymerase chain reaction (PCR) techniques. RESULTS: Clonal T-cell expansion was detected in 7 patients with SS by immunostaining of the TCR V beta regions. PCR analysis confirmed the presence of dominant T cell clones. Double-immunostaining revealed that in each case cells of the clonal V beta TCR rearrangement homogeneously express the CD4(+)CD7(-) phenotype. Furthermore, CD4(+)CD7(-) cells express the CD15s antigen but lack expression of CD26 and CD49d. CONCLUSION: Expansion of clonal T cells strongly correlates with the expansion of CD4(+)CD7(-) T cells in 7 tested patients with SS. This supports our model that a subset of late differentiated, normal CD4(+)CD7(-) memory T cells may represent the physiologic counterpart of Sézary cells. Monitoring of circulating T cells with the CD4(+)CD7(-)CD15s(+)CD26(-)CD49d(-) phenotype proved to be useful for the identification of clonal T cells in patients with SS.     

Dermal fibroblasts sustain proliferation of activated T cells via membrane-bound interleukin-15 upon long-term stimulation with tumor necrosis factor-alpha

In chronic inflammatory conditions, mononuclear cells infiltrate the connective tissue attracted by fibroblast-secreted chemokines. The role of fibroblasts in sustaining the lymphocyte immune response upon cellular infiltration is so far unresolved. We here report that, upon prolonged stimulation with tumor necrosis factor-alpha, dermal fibroblasts enhance proliferation of activated T cells whereas unstimulated fibroblasts do not. T cell growth stimulation requires cell contact of tumor necrosis factor-alpha stimulated fibroblasts to T cells and is not due to soluble factors. Growth stimulation is substantially blocked by neutralizing antibodies to interleukin-15. Fluorescence-activated cell sorter analyses revealed that tumor necrosis factor alpha stimulated fibroblasts expose interleukin-15 in a membrane-bound form on the cell surface whereas nonstimulated fibroblasts and interferon-gamma treated fibroblasts do not. The amount of membrane interleukin-15 increases with the duration of tumor necrosis factor-alpha stimulation for at least 3 d. Unstimulated fibroblasts, however, accumulate interleukin-15 in the cytoplasm. No interleukin-15 could be detected in the culture supernatant. Immunohistochemical analyses confirmed membrane interleukin-15 on dermal fibroblasts in discoid lupus erythematosus skin lesions whereas no membrane interleukin-15 was found on the surface of fibroblasts in healthy skin. We conclude that dermal fibroblasts upon long-term tumor necrosis factor-alpha stimulation during chronic inflammation are involved via membrane-bound interleukin-15 in stimulating proliferation of accumulated, activated T cells.