Monitoring of physical activity and heart rate variability in patients with chronic heart failure using cardiac resynchronization devices

Cardiac resynchronization therapy (CRT) devices not only deliver effective treatment but may also serve as valuable diagnostic tools in heart failure management. In the present study, the minutes of daily physical activity and heart rate variability, measured by sensors incorporated into such a device, reflected the effects of CRT and were related to New York Heart Association functional class.     

Free reactive oxygen species and nephrotoxicity of contrast agents

BACKGROUND: The nephrotoxicity induced by contrast media remains a serious clinical problem, and the underlying mechanism has not been completely understood. Experimental and clinical investigations suggest that reactive oxygen species (ROS) are critical determinants of radiocontrast nephropathy (RCN), and that antioxidants can prevent this damage. METHODS: Cultured human proximal renal tubule cells (HK-2) were exposed to hydrogen peroxide (H2O2) at different concentrations. H2O2-induced tubular DNA damage was examined in the presence of the antioxidant MESNA (sodium-2-mercaptoethane sulphonate). The induction of DNA damage was measured with the alkaline comet assay (single cell gel electrophoresis). We also studied 12 patients with stable renal impairment (median baseline creatinine 296 micromol/l; range: 203-495 micromol/l) undergoing cardiac catheterization/intervention prospectively. Patients received 800 mg MESNA intravenously 30 min before exposure to the contrast agent in addition to 0.9% saline hydration. RESULTS: In the cell cultures, oxidative stress on HK-2 cells induced increased DNA migration in the comet assay. Treatment of tubular cells with the antioxidant MESNA prior to the addition of H2O2 significantly reduced DNA migration in the comet assay. In the clinical study, treatment of the patients with MESNA prevented the adverse renal effect of contrast media (median serum creatinine 293; range: 187-433 micromol/l) 48 h after coronary angiography/intervention. CONCLUSION: Both the in vivo and the in vitro studies suggest that the ROS-mediated renal injury could be inhibited by a potent antioxidant such as MESNA.     

Biotransformation of N-(2-alkylamino-4-phenylimidazol-1-yl)-acetamides and kinetic studies by using cells and laccase from Trametes versicolor

The product pattern of biotransformation of different N-(2-alkylamino-4-phenylimidazol-1-yl)-acetamides were compared. N-(2-alkylamino-4-phenylimidazol-1-yl)-acetamides were transformed by Trametes versicolor into two types of aromatic products identified by chemical structure analysis: 1. Novel heteroaromatic compounds, such as: 2-(alkylamino)-4-phenylimidazoles, N-(2-alkylamino-5-formyl-4-phenylimidazol-1-yl)-acetamides, N-(2-alkylimino-3-hydroxy-4-phenyl-2,3-dihydroimidazol-1-yl)-acetamides and N-(2-alkylimino-5-oxo-4-phenyl-2,5-dihydroimidazol-1-yl)-acetamides, 2. Novel compounds arising from coupling of two molecules of the substrate. These aromatic compounds were produced from the beginning of incubation by cultures of T. versicolor. In addition to these two types of biotransformation products, monoaromatics such as oxophenyl acetic acid, benzoic acid, and benzyl alcohol were formed as degradation products resulting from an extended incubation of the substrates and from the degradation of the first two types of transformation products. Crude preparations of laccase from T. versicolor catalysed only the formation of novel heteroaromatic compounds, though they do so with higher yields and in shorter time than cultures of T. versicolor.     

Site-specific human breast cancer (MDA-MB-231) metastases in nude rats: model characterisation and in vivo effects of ibandronate on tumour growth

Animal models are important tools to study the development of bone metastases and to evaluate strategies for their prevention and treatment. We here describe a new model in which tumour inoculation is achieved by injection of cancer cells into the femoral artery. This approach results in the development of multiple osteolytic lesions in the distal femora and proximal tibiae within 18 days after inoculation, with a success rate of 95-100% and no additional comorbidity. In untreated animals, osteolyses expanded continuously at a growth rate of 4.7-8.2 mm(2)/4 days, causing extensive destruction of resident bone structures by the tumour, significant loss of tibial bone density and a transient rise in urinary bone resorption markers. Continuous daily treatment with ibandronate (10 microg/kg) inhibited further growth of fully established metastases and reduced the mean osteolytic growth rate to 0.03 mm(2)/4 days. In lesions <6 mm bisphosphonate treatment resulted in a negative growth rate (-0.33 to -0.81 mm(2)/4 days). When ibandronate was started 3 days prior to tumour cell inoculation, the development of osteolytic lesions was substantially reduced (take rate only 17%) and bone density and structure were mostly preserved. We conclude that the intra-arterial approach used in this new model of metastatic bone disease results in site-specific osteolytic lesions with high take rates, steady tumour growth and no additional morbidity. While serial bone marker assessments did not prove useful to monitor osteolytic growth, our studies provide in vivo evidence that ibandronate treatment induces tumour remission by reversal of tumour growth.     

In vivo measurement of oxygen-derived free radicals during reperfusion injury

By use of an optimized cytochrome c-based biosensor, superoxide radical production was measured continuously in vivo. The aim of this study was the online detection of superoxide concentration during reperfusion after a variable time of ischemia. Measurements were performed by placing the detecting sensor into gastrocnemius muscle tissue. Ischemia was induced by clamping the vena and arteria femoralis. Current response of the sensor was recorded continuously as an equivalent for superoxide concentration. Ischemia times varied from 5 to 120 minutes. The minimum ischemia time to record superoxide production was 10 minutes. By inducing longer periods of ischemia, an increase in superoxide concentration reached its highest levels at 2 hours. Furthermore, the total time of superoxide production after reperfusion depended on the total time of ischemia.     

Increased expression of TGF-beta1 and IGF-I in inflammatory stenotic lesions of hemodialysis fistulas

BACKGROUND: Hemodialysis fistula dysfunction due to stenotic lesions remains a frequent cause of hospitalization for hemodialysis patients. Transforming growth factor-beta(TGF-beta) and insulin-like growth factor-I (IGF-I) are known to be involved in atherogenesis. The latent TGF-beta1 binding protein-1 (LTBP-1) targets extracellular matrix (ECM) interactions and is involved in the regulation of TGF-beta latency. METHODS: We investigated the expression of TGF-beta1, LTBP-1 and IGF-I in 15 occluded or severely narrowed vein segments of primary arteriovenous fistulas, in 29 non-stenosed control veins from uremic, pre-dialysis patients, and in 15 non-stenosed control saphenous veins obtained from patients undergoing aortocoronary bypass grafting. Immunohistochemistry was performed on snap-frozen tissue specimens using antibodies recognizing either the latency-associated peptide of TGF-beta1 (96-1), LTBP-1 (Ab39) or IGF-I. Serum levels of TGF-beta1 and IGF-I were determined by commercially available IRMA. RESULTS: In stenosed hemodialysis fistulas, a pronounced intimal thickening with deposition of ECM was observed with light and electron microscopy. Infiltrating cells were seen in stenosed vessels, mostly in areas of intimal hyperplasia and in the media. TGF-beta1, LTBP-1 and IGF-I expression were mostly localized in the neointimal and medial layers, and were significantly higher than in the control groups. A positive correlation between the presence of inflammatory cells and the staining intensity for TGF-beta1, LTBP-1 and IGF-I was found in all vessels analyzed. CONCLUSION: Neointimal thickening of primary arteriovenous fistulas represents a local inflammatory process and appears to be associated with increased protein expression of TGF-beta1 and IGF-I. While local IGF-I is likely to stimulate smooth muscle cell proliferation in this setting, TGF-beta1 may be an important trigger of ECM production and deposition.     

Changes in rabbit corneal epithelial membrane permeability caused by locally applied Pseudomonas aeruginosa cytotoxin: a microfluorometric examination in vivo

The effects of a poreforming protein from Pseudomonas aeruginosa on the rabbit cornea were tested in vivo by measuring intraepithelial carboxyfluorescein accumulation. Carboxyfluorescein diacetate and subsequently the P. aeruginosa cytotoxin were applied by means of contact lenses with a spherical cavity on the concave surface. This allowed the application of defined concentrations of carboxyfluorescein diacetate and cytotoxin on a defined area of the corneal epithelium. Starting at 0.5 M, cytotoxin increased the epithelial cell membrane permeability for the intracellular carboxyfluorescein within 1 min. At higher concentrations cells were shed from the epithelium. Corresponding morphological changes of the cellular structure of the corneal epithelium were observed and documented by fluorescence photomicrography. The healing process of toxified corneal epithelium appeared to be complete within 3 days. The data presented here indicate the possible role of cytotoxin-induced changes in epithelial permeability in P. aeruginosa infections. In this context, the role of soft contact lenses as a possible cytotoxin reservoir is discussed.     

Enhanced excretion of intermediates of aromatic amino acid catabolism during chlorophenol degradation due to nutrient limitation in the yeast Candida maltosa

Incubation of phenol-induced cells of the yeast Candida maltosa SBUG 700 with mono- and dichlorophenols resulted in the formation of metabolites of the substrates and of further metabolites not related to the degradation pathway of the substrates. These additional compounds, identified as 4-hydroxyphenylacetic acid (4-HPA), phenylacetic acid (PA), indolylacetic acid (IA) and indolylethanol (IE) by means of HPLC and GC/MS, were not excreted in incubation experiments with glucose. The excretion of these metabolites of aromatic amino acid metabolism is not caused by toxic effects of the phenol derivatives, but seems to be a result of carbon and nitrogen starvation of yeast cells.     

Antibody diversification

Antibody diversification processes play a major role in protecting humans from pathogenes. Somatic hypermutation and gene conversion increase the affinity of pathogen-specific antibodies by changing the sequence within antibody variable genes, while the class switch recombination (CSR) process changes the antibody's effector function by replacing the constant region of the antibody gene with a different constant region. Activation-induced cytidine deaminase (AID) initiates each of these three processes by deaminating cytidines within antibody genes, while a host of other DNA transacting factors are involved in either creating new mutations or repairing DNA lesions introduced during these processes. This review will discuss the main features of antibody diversification and their role in lymphomagenesis, highlight outstanding issues and questions that remain in the field and discuss our contributions to this field.