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Berbanes: search for novel alpha-2 adrenoceptor antagonists

We have previously described the alpha-2 adrenoceptor antagonist properties of berbanes and its stereoisomers. Of the compounds studied CH-38083 (2,3-methylenedioxy-11-betahydroxyalloberbane) has been selected for further analysis based upon its high affinity and selectivity for central and peripheral alpha-2 adrenoceptors. Structure activity relationship study revealed that the aromatic ring with its substituents at C-2 and C-3 positions, the nitrogen atom, the hydroxy group at C-11 position and the methoxycarbonyl group at C-12 position are important for the binding of the berbanes to the alpha-2 adrenoceptors. Using alloberbane derivatives for characterization of the alpha-2 adrenoceptors it was speculated that xylazine sensitive alpha-2 adrenoceptors in the rat vas deferens and in the guinea-pig ileum are similar, whereas xylazine sensitive and noradrenaline sensitive alpha-2 adrenoceptors of the guinea-pig ileum may belong to different subtypes. Correlation studies indicated that modification of the molecular structure of the alloberbanes can lead to either increased or decreased alpha-2 adrenoceptor antagonists activity without parallel changes in the alpha-1 adrenoceptor antagonist potency. The low affinity of CH-38083 for other receptor populations (muscarinic, histamine, dopamine receptors) makes this compound attractive for investigation of alpha-2 adrenoceptor-mediated neural processes in the central nervous system and periphery.     

Pancreatic transplant imaging

Forty-four clinical episodes of suspected (pancreas) transplant rejection in 17 pancreatic transplantation patients were reviewed retrospectively. The clinical impression of acute graft rejection, chronic rejection, or nonrejection in each episode was correlated with the results of 19 nuclear medicine, 12 ultrasound (US), and 44 magnetic resonance (MR) imaging studies. US was found to be a moderately sensitive (82%) method of detecting graft rejection. US also was effective in identifying intra- and peripancreatic fluid accumulations. Nuclear medicine imaging was also a sensitive technique (86%) and the only modality that provided physiologic information regarding graft perfusion. MR imaging allowed correct prediction of the presence or absence of graft rejection in 39 of 44 cases (sensitivity, 100%; specificity, 76%) and was an effective means of detecting pathologic fluid collections. Nuclear medicine, US, and MR imaging are all believed to be sensitive methods of detecting graft rejection and are complementary adjuncts to the clinical evaluation of pancreatic transplants.     

Inhibition by deprenyl of dopamine uptake in rat striatum: a possible correlation between dopamine uptake and acetylcholine release inhibition

Optical isomers of deprenyl inhibit the resting and ouabain induced release of acetylcholine (ACh) in isolated striatal slices of the rat and this effect correlates with the capability of deprenyl to inhibit the uptake of 3H-dopamine in striatal homogenate in a concentration of 10(-4)--10(-4) M. The release of ACh is significantly increased in striatal slices taken from rats pretreated with a single dose of 250 micrograms of 6-hydroxydopamine. 5 mg/kg of deprenyl given 30 min prior to 6-hydroxydopamine treatment prevented completely the chemical destruction of the dopaminergic neurons. In contrast to deprenyl, clorgyline potentiated the effect of 6-hydroxydopamine.     

Lactobacillus rhamnosus CNCM I-3690 and the commensal bacterium Faecalibacterium prausnitzii A2-165 exhibit similar protective effects to induced barrier hyper-permeability in mice

Impaired gut barrier function has been reported in a wide range of diseases and syndromes and in some functional gastrointestinal disorders. In addition, there is increasing evidence that suggests the gut microbiota tightly regulates gut barrier function and recent studies demonstrate that probiotic bacteria can enhance barrier integrity. Here, we aimed to investigate the effects of Lactobacillus rhamnosus CNCM I-3690 on intestinal barrier function. In vitro results using a Caco-2 monolayer cells stimulated with TNF-α confirmed the anti-inflammatory nature of the strain CNCM I-3690 and pointed out a putative role for the protection of the epithelial function. Next, we tested the protective effects of L. rhamnosus CNCM I-3690 in a mouse model of increased colonic permeability. Most importantly, we compared its performance to that of the well-known beneficial human commensal bacterium Faecalibacterium prauznitzii A2-165. Increased colonic permeability was normalized by both strains to a similar degree. Modulation of apical tight junction proteins expression was then analyzed to decipher the mechanism underlying this effect. We showed that CNCM I-3690 partially restored the function of the intestinal barrier and increased the levels of tight junction proteins Occludin and E-cadherin. The results indicate L. rhamnosus CNCM I-3690 is as effective as the commensal anti-inflammatory bacterium F. prausnitzii to treat functional barrier abnormalities.     

Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with non-Hodgkin's lymphoma

A prospective comparative trial of allogeneic versus autologous bone marrow transplant (BMT) was conducted. Sixty-six consecutive patients (median age, 41; range, 15 to 60; female:male ratio = 21:45) entered this clinical trial. Priority for allogeneic BMT was given to patients who were 55 or younger and had a major histocompatibility complex- matched or 1-antigen-disparate sibling donor. Autologous BMT was offered to all other patients whose age was 60 or younger. Patients who had no sibling donor and who had BM involvement at the time of evaluation were not eligible. Thirty-one patients received an allograft, and 35 patients received an autograft. Thirteen patients received a BM graft purged with 4-hydroperoxycyclophosphamide because of previous BM involvement. Patients who had previous radiation to the thoracic and/or abdominal areas of more than 20 Gy received a preparative regimen consisting of cyclophosphamide (1,800 mg/m2/d for 4 days), VP-16 (200 mg/m2 every 12 hours for 8 doses), and 1,3-bis(2- chloroethyl)-1-nitrosourea (600 mg/m2 as 1 dose). Other patients received cyclophosphamide 1,800 mg/m2/d for 4 days followed by total body irradiation of 12 Gy administered as a single daily fraction over 4 days. With a median follow-up of 14 months, the progression-free survival (PFS) for autograft and allograft recipients was 24% +/- 8% (+/- SE) and 47% +/- 9%, respectively, (P = .21). However, the probability of disease progression was significantly higher in the autologous group (69% +/- 9%) than in the allogeneic group (20% +/- 10%; P = .001). When other confounding prognostic factors were adjusted in the multivariate analysis, chemosensitive disease and allograft were found to have a significant favorable influence on probability of disease progression (P = .03 and .003), but only chemosensitive disease had a significant influence on the PFS (P < .002). Our results suggest the existence of graft-versus-lymphoma effect and also support the rationale of using immunotherapy after autologous BMT. Allogeneic BMT should be preferable to autologous BMT in younger patients with lymphoma.