Renale Wirkungen von Acetazolamid,Chlorothiazid und Chlormerodrin bei experimenteller Niereninsuffizienz

Zusammenfassung Nach Darstellung der klinischen Befunde über die Wirkung von Acetazolamid, Chlorothiazid und Chlormerodrin bei Niereninsuffizienz werden die Änderungen der Wirkungen der Diuretica durch Strahlermephritis, Pyelonephritis oder partielle Nephrektomie im Tierversuch besprochen.Bei Strahlennephritis nahm die Quecksilberwirkung, namentlich der diuretische und natriuretische Effekt ab, nach Parenchymresektion trat nach kurzer normaler Wirksamkeit rasch eine toxische Nierenschädigung mit Retention von Kochsalz und Wasser ein.Acetazolamid und Chlorothiazid zeigten dagegen Effekte, die bei allen Schädigungen in die gleiche Richtung wie bei intakten Tieren gingen, deren Größe aber je nach gewähltem Maßsystem (absolute oder prozentuale Mehrausscheidung, bzw. Änderung der tubulären Rückresorption ausgedrückt als Prozent der filtrierten Menge) variiert. Ein Urteil über stärkere oder schwächere Wirkungen nach den einzelnen Schädigungen kann daher nicht gefällt werden; ein totaler Wirkungsverlust fand sich in keinem Fall.Da Chlorothiazid nach allen Nierenschädigungen am wenigsten von seiner Wirkung verlor und keine Intoxikationen hervorrief, darf es am günstigsten von den untersuchten Diuretica beurteilt werden.     

Transmural metabolite distribution in regional myocardial ischemia as studied with 31P NMR

Phosphorus-31 nuclear magnetic resonance (31P NMR) has been applied to study the canine heart prior to and during regional myocardial ischemia induced by partial flow reduction in the left anterior descending coronary artery (LAD). NMR data were acquired in a transmural fashion by restricting the signal to a column perpendicular to the heart wall using B0 gradients and obtaining spectroscopic spatial resolution along the third dimension using the B1 gradient and adiabatic excitation. With this approach, transmural spectra were accumulated in five separate voxels spanning the wall of the left ventricle from the epicardium to the endocardium. In the normal canine myocardium the levels of high-energy phosphates CP and ATP were relatively constant throughout the left ventricular wall, with only minor evidence of free inorganic phosphate in any of the transmural voxels. However, during sustained partial occlusion of the LAD, significant regional differences between the epi- and the endocardium were noted. The data demonstrate the importance of studying cardiac bioenergetics with transmural differentiation.     

NEMO expression in human hepatocellular carcinoma and its association with clinical outcome

The nuclear factor κ-light-chain enhancer of activated B-cells (NF-κB) signaling pathway is regarded as an important factor in inflammation and carcinogenesis. Recently, a role in hepatocarcinogenesis has been attributed to the NF-κB regulatory subunit IKKγ (NEMO) using knockout mice. However, a detailed investigation of NEMO expression in human hepatocellular carcinomas (HCCs) has not yet been reported. We selected 85 HCC patients who had undergone curative liver resection and analyzed NEMO expression of the respective tumors by immunohistochemistry, Western blotting, and real-time PCR. NEMO expression was correlated with clinicopathological parameters, and the impact on 5-year disease-free survival and 5-year overall survival was calculated using multivariate Cox proportional models. In our study, complete loss of NEMO immunoreactivity was found in 34 (40%) of 85 HCCs compared with their adjacent nonneoplastic tissue (P < .05). NEMO messenger RNA (mRNA) expression was detected in all HCC cases; however, no correlation between NEMO immunoreactivity and mRNA level was found. Five-year overall survival rates for patients with low and high NEMO expression were 22% and 50%, respectively (P = .049). However, high tumor stage, but not level of NEMO expression, was confirmed as an independent poor prognostic factor for 5-year disease-free survival (hazards ratio [HR] = 2.1, 95% confidence interval [CI] = 1.3-3.6, P = .009) and 5-year overall survival (HR = 2.5, CI = 1.4-4.4, P = .002). In conclusion, a loss of NEMO immunoreactivity occurs in a substantial proportion of human HCCs. Although low NEMO expression is correlated with a poor 5-year overall survival in patients with HCC, NEMO cannot be regarded as an independent prognostic marker for predicting the clinical outcome of patients suffering from HCC.     

Transmit B1‐field correction at 7T using actively tuned coupled inner elements

When volume coils are used for ¹H imaging of the human head at 7T, wavelength effects in tissue cause a variation in intensity, that is typically brighter at the center of the head and darker in the periphery. Much of this image nonuniformity can be attributed to variation in the effective transmit B₁ field, which falls by ～ 50% to the left and right of center at mid‐elevation in the brain. Because most of this B₁ loss occurs in the periphery of the brain, we have explored use of actively controlled, off‐resonant loop elements to locally enhance the transmit B₁ field in these regions. When tuned to frequencies above the NMR frequency, these elements provide strong local enhancement of the B₁ field of the transmit coil. Because they are tuned off‐resonance, some volume coil detuning results, but resistive loading of the coil mode remains dominated by the sample. By digitally controlling their frequency offsets, the field enhancement of each inner element can be placed under active control. Using an array of eight digitally controlled elements placed around a custom‐built head phantom, we demonstrate the feasibility of improving the B₁ homogeneity of a transmit/receive volume coil without the need for multiple radio frequency transmit channels. Magn Reson Med, 2011. © 2011 Wiley‐Liss, Inc.     

The changing scene of allogeneic stem cell transplantation for chronic myeloid leukemia—a report from the German Registry covering the period from 1998 to 2004

Due to the recent changes in the indication to allogeneic stem cell transplantation (SCT) in chronic myeloid leukemia (CML), we retrospectively analyzed 1,716 patients with different CML stages who received an allograft from related (n?=?767) or unrelated donors (n?=?938) within the German Registry of Stem Cell Transplantation (DRST) from 1998 to 2004. Myeloablative conditioning was performed in 724/871 cases (83%), dose-reduced conditioning in 147/871 (17%). Annual transplantations were decreasing from 357 to 98 (28%) in the period of study, but the proportion of advanced cases was increasing from 32% (112/346) to 53% (50/94) of all SCTs. Stage of disease, intervals from diagnosis, and patients’ age were independent prognostic parameters, while peripheral stem cells and unrelated transplantation seemed equal to bone marrow/related transplantation. This study demonstrates that allo-SCT still has an important role in advanced CML, which emphasizes the need for optimized transplantation strategies for these high-risk patients.     

Experimental autoimmune encephalomyelitis in mice expressing the autoantigen MBP 1-10 covalently bound to the MHC class II molecule I-Au

Most autoantigens implicated in multiple sclerosis (MS) are expressed not only in the central nervous system (CNS) but also in the thymus and the periphery. Nevertheless, these autoantigens might induce a strong autoimmune response leading to severe destruction within the CNS. To investigate the influence of a dominantly presented autoantigen on experimental autoimmune encephalomyelitis (EAE), we generated transgenic mice expressing the autoantigenic peptide MBP 1-10 covalently bound to the MHC class II molecule I-Au. These mice were crossed either with B10.PL or with TCR-transgenic Tg4 mice, specific for the transgenic peptide-MHC combination. In double transgenic mice we found strong thymic deletion and residual peripheral T cells were refractory to antigen stimulation in vitro. Residual peripheral CD4+ T cells expressed activation markers and a high proportion was CD25 positive. Transfer of both CD25-negative and CD25-positive CD4+ T cells from double transgenic animals into B10.PL mice strongly inhibited the progression of EAE. Despite this thorough tolerance induction, some double transgenic mice developed severe signs of EAE after an extended period of time. Our data show that in the circumstances where autoantigenic priming persists, and where the number of antigen-specific T cells is high enough, autoimmunity may prevail over very potent tolerance-inducing mechanisms.     

Angiopoietins: a link between angiogenesis and inflammation

The angiopoietin (Ang)-Tie ligand-receptor system has a key regulatory role in regulating vascular integrity and quiescence. Besides its role in angiogenesis, it is an important regulator in numerous diseases including inflammation. Ang-1-mediated Tie2 activation is required to maintain the quiescent resting state of the endothelium. Agonistic Ang-1 functions are antagonized by Ang-2, which is believed to inhibit Ang-1-Tie2 signaling. Ang-2 destabilizes the quiescent endothelium and primes it to respond to exogenous stimuli, thereby facilitating the activities of inflammatory (tumor necrosis factor and interleukin-1) and angiogenic (vascular endothelial growth factor) cytokines. Intriguingly, Ang-2 is expressed weakly by the resting endothelium but becomes strongly upregulated following endothelial activation. Moreover, endothelial cells store Ang-2 in Weibel-Palade bodies from where it can be made available quickly following stimulation, suggesting a role of Ang-2 in controlling rapid vascular adaptive processes. This suggests that Ang-2 is the dynamic regulator of the Ang-Tie2 axis, thereby functioning as a built-in switch controlling the transition of the resting quiescent endothelium towards the activated responsive endothelium.     

CD8+ regulatory T cells generated by neonatal recognition of peripheral self-antigen

In comparison with CD4+ regulatory T cells, the generation and function of immunomodulatory CD8+T cells is less well defined. Here we describe the existence of regulatory anti-Kb-specific CD8+ T cells that are rendered tolerant during neonatal life via antigen contact exclusively on keratinocytes. These regulatory T cells maintain tolerance during adulthood as they prevent Kb-specific graft rejection by na?ve CD8+ T cells. Third-party immune responses remain unaffected. Up-regulation of TGF-beta1 and granzyme B in the regulatory CD8+ T cell population suggests the involvement of these molecules in common suppressive pathways shared with CD4+ regulatory T cells. In summary, CD8+ regulatory T cells can be induced extrathymically through antigen contact on neonatally accessible parenchymal cells and maintain tolerance throughout adult life.     

Proliferative activity in stenotic human aortocoronary bypass grafts.

BACKGROUND: Aortocoronary bypass graft disease is responsible for long-term failure of autologous vein grafts. The analyses of proliferation and cell type characterisation in human bypass grafts harvested during re-do surgery make it possible to investigate the cellular processes leading to bypass graft failure. METHODS: 30 stenotic vein grafts and 25 control veins were explantated during re-do heart surgery procedures. The total area and cell count of the neointima, media and adventitia were calculated computer-assisted. Actively proliferating cells were identified using antibody to Ki-67 and positive cells were determined by double-label immunocytochemistry with SMC alpha-actin, CD 31 (endothelial cells), CD 68 (macrophages) and CD 45 (T-lymphocytes). RESULTS: Active proliferation was detected in different cell types with an average proliferation index of 0.15%, 0.18% and 0.086% for neointima, media and adventitia. Only 9% of proliferating cells in the neointima were SMC (not identified cells 40%); correspondingly, 14% SMC (not identified cells 33%) were detected in the media. Endothelial cells turned out to be the predominant proliferating cell type in all sections of the vessel wall. CONCLUSION: Proliferation in our series of stenotic vein grafts occurred at a low level, but was significantly higher compared to native control veins. While proliferation may play an important role in early lesions, our data clearly show low proliferation activity in advanced graft lesions. The identification of proliferating macrophages and T-lymphocytes implicate an additional inflammatory component in the development of human bypass graft disease. SUMMARY: To clarify the role of cellular proliferation in human aortocoronary bypass grafts, we characterized the cellular composition and proliferation index in 30 stenotic saphenous vein grafts in comparison to 25 native veins. Proliferation in our series of stenotic vein grafts occurred at a low level, but was significantly higher compared to native control veins.