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In critically ill patients regulation of heart-rate is often severely disturbed. Interaction of bacterial endotoxin (lipopolysaccharide, LPS) with hyperpolarization-activated cyclic nucleotide-gated cation-(HCN)-channels may interfere with heart-rate regulation. This study analyzes the effect of LPS, the HCN-channel blocker ivabradine or Ca(2+) -channel blockers (nifedipine, verapamil) on pacemaking in spontaneously beating neonatal rat cardiomyocytes (CM) in vitro. In vivo, the effect of LPS on the heart-rate of adult CD1-mice with and without autonomic blockade is analyzed telemetrically. LPS (100 ng/mL) and ivabradine (5 μg/mL) reduced the beating-rate of CM by 20.1% and 24.6%, respectively. Coincubation of CM with both, LPS and ivabradine, did not further reduce the beating-rate, indicating interaction of both compounds with HCN-channels, while coincubation with Ca(2+) -channel blockers and LPS caused additive beating-rate reduction. In CD1-mice (containing an active autonomic-nervous-system), injection of LPS (0.4 mg/kg) expectedly resulted in increased heart-rate. However, if the autonomic nervous system was blocked by propranolol and atropine, in line with the in vitro data, LPS induced a significant reduction of heart-rate, which was not additive to ivabradine. The in vivo and in vitro results indicate that LPS interacts with HCN-channels of cardiomyocytes. Thus, LPS indirectly sensitizes HCN-channels for sympathetic activation (tachycardic-effect), and in parallel directly inhibits channel activity (bradycardic-effect). Both effects may contribute to the detrimental effects of septic cardiomyopathy and septic autonomic dysfunction., (© 2015 Wiley Publishing Asia Pty Ltd.)

Renal tubular handling of urate is realized by a network of uptake and efflux transporters, including members of drug transporter families such as solute carrier proteins and ATP-binding cassette transporters. Solute carrier family 2, member 9 (SLC2A9), is one key factor of this so called "urate transportosome." The aim of the present study was to understand the transcriptional regulation of SLC2A9 and to test whether identified factors might contribute to a coordinated transcriptional regulation of the transporters involved in urate handling. In silico analysis and cell-based reporter gene assays identified a hepatocyte nuclear factor (HNF)4α-binding site in the promoter of SLC2A9 isoform 1, whose activity was enhanced by transient HNF4α overexpression, whereas mutation of the binding site diminished activation. HNF4α overexpression induced endogenous SLC2A9 expression in vitro. The in vivo role of HNF4α in the modulation of renal SLC2A9 gene expression was supported by findings of quantitative real-time RT-PCR analyses and chromatin immunoprecipitation assays. Indeed, mRNA expression of SLC2A9 and HNF4α in human kidney samples was significantly correlated. We also showed that in renal clear cell carcinoma, downregulation of HNF4α mRNA and protein expression was associated with a significant decline in expression of the transporter. Taken together, our data suggest that nuclear receptor family member HNF4α contributes to the transcriptional regulation of SLC2A9 isoform 1. Since HNF4α has previously been assumed to be a modulator of several urate transporters, our findings support the notion that there could be a transcriptional network providing synchronized regulation of the functional network of the urate transportosome., (Copyright © 2014 the American Physiological Society.)

Background: D(2) receptor function can be assessed by growth hormone (GH) response to apomorphine. Several association studies between dopamine receptor polymorphisms and results of the apomorphine challenge test with normal and alcohol-dependent subjects yielded inconsistent results. In this pilot study, we tested polymorphisms from the DRD2 region for GH response to apomorphine challenge in more detail., Methods: Apomorphine challenge tests measuring GH responses on 5 time points were performed on day 1 of alcohol detoxification in 43 patients with alcohol dependence; patients were genotyped for 11 polymorphisms including DRD2, ANKK1, NCAM1 and TTC12., Results: Associations (p<0.05) were found for ANKK1 (rs11604671, rs1800497) and DRD2 (rs6276, rs1076560), which are located on adjacent chromosomal positions. Consistent with PET studies suggesting a reduced D(2) receptor availability in patients carrying the ANKK1 rs1800497 T polymorphism (formerly known as DRD2 TaqI A1) we found a reduced GH response to apomorphine in those subjects., Conclusion: This has been the first study showing significant associations between apomorphine-induced GH response and SNPs in DRD2 and ANKK1 in alcohol-dependent patients. In this respect, our preliminary results are in line with other reports which suggested that DRD2 and ANKK1 polymorphisms influence D(2) receptor availability and signal transduction in the dopaminergic pathways. Small sample size in our study limits the generalizability of our results., (Copyright 2009 Elsevier Inc. All rights reserved.)

Background: Heterotrimeric G proteins are key mediators of signals from membrane receptors-including the thyroid-stimulating hormone (TSH) receptor-to cellular effectors. Gain-of-function mutations in the TSH receptor and the Galpha(S) subunit occur frequently in hyperfunctioning thyroid nodules and differentiated thyroid carcinomas, whereby the T allele of a common polymorphism (825C>T, rs5443) in the G protein beta3 subunit gene (GNB3) is associated with increased G protein-mediated signal transduction and a complex phenotype. The aim of this study was to investigate whether this common polymorphism affects key parameters of thyroid function and morphology and influences the pathogenesis of thyroid diseases in the general population., Methods: The population-based cross-sectional Study of Health in Pomerania is a general health survey with focus on thyroid diseases in northeast Germany, a formerly iodine-deficient area. Data from 3428 subjects (1800 men and 1628 women) were analyzed for an association of the GNB3 genotype with TSH, free triiodothyronine and thyroxine levels, urine iodine and thiocyanate excretion, and thyroid ultrasound morphology including thyroid volume, presence of goiter, and thyroid nodules., Results: There was no association between GNB3 genotype status and the functional or morphological thyroid parameters investigated, neither in crude analyses nor upon multivariable analyses including known confounders of thyroid disorders., Conclusions: Based on the data from this large population-based survey, we conclude that the GNB3 825C>T polymorphism does not affect key parameters of thyroid function and morphology in the general population of a formerly iodine-deficient area.

Background: The hypocretin receptor 2 (HCRTR2) G1246A polymorphism has been associated with the risk for cluster headache. Since the hypothalamic hypocretin/orexin system projects throughout the nervous system and affects multiple vegetative functions including generation of rhythmicity, vasomotion, autonomic symptoms as well as modulation of nociception, it may also be linked with migraine., Objective: We thus sought to evaluate whether the HCRTR2 G1246A polymorphism is associated with the risk for migraine., Methods: We prospectively established a cohort of 146 unrelated patients with migraine. The control group consisted of 279 healthy volunteers. We genotyped patients and controls for the HCRTR2 G1246A polymorphism and examined an association with presence or absence of migraine., Results: Genotype and allele frequencies were not significantly different between migraine patients and controls (genotype distribution: chi(2)= 4.13, 2 df, P= .13; allele distribution: chi(2)= 0.9, 1 df, P= .34)., Conclusion: Our study does not support a major contribution of the HCRTR2 G1246A polymorphism to the pathogenesis of migraine in contrast to its effects in cluster headache.

Contrary to the findings of Herbert et al. (Reports, 14 April 2006, p. 279), homozygous carriers of the C allele of the rs7566605 variant near the INSIG2 gene did not exhibit a significantly increased risk for obesity in a large population-based cross-sectional German study. A subgroup analysis, however, revealed that this allele significantly increased the risk for obesity in already overweight individuals.

Background: Vascular endothelial cells of man and pig, but not rodents, strongly express major histocompatibility complex (MHC) class II antigens in vivo, probably via the inducible promoter IV of the class II transactivator. There is abundant in vitro evidence that MHC class II positive vascular endothelial cells can activate T cells. Peripheral antigen presentation by endothelial cells is potentially important for organ-specific immunity, for allograft rejection, and possibly for immune responsiveness in general. Given the reported effects of statins on promoter IV of the class II transactivator, we evaluated in vivo expression of MHC class II antigens in pigs treated with atorvastatin calcium., Methods: Pigs were given 3 mg/kg/day of atorvastatin orally daily for 16 days, and then killed 24 hr after the last dose. Heart, kidney, and liver were removed for immunohistological and quantitative absorption analysis., Results: Double-labeling studies using immunofluorescence on frozen section for Factor VIII and MHC class II showed a marked suppression of MHC class II on vascular endothelial cells in all 4 treated pigs, in comparison with untreated pigs. This was confirmed using immunoperoxidase techniques on frozen sections. Quantitative absorption analysis showed up to 25-fold reduction in MHC class II expression., Conclusions: Statins substantially suppress endothelial cell MHC class II expression in vivo. This is likely to inhibit organ-specific immune responses, and possibly also general immune responsiveness. In a transplantation setting, in addition to other regulatory effects on the recipients immune system, statins might reduce the long-term capacity of the donor organ to activate rejection mechanisms.

Xenogeneic anti-lymphocyte serum (ALS) remains a major reagent for immunosuppression in clinical practice, but mechanisms of action and risks of opportunistic infection have not been considered in the context of innate immunity and its role in immune responsiveness. Rabbit anti rat ALS was administered intraperitoneally. Blood was taken for flow cytometry to establish absolute counts of leucocyte subsets. Tissues were harvested for immunohistology to evaluate interstitial dendritic cells and tissue macrophages. At day 2 of ALS therapy, T cells are completely depleted, as anticipated. B cells are undiminished and form approximately 90% of blood leucocytes. Monocytes and natural killer (NK) cells are substantially (approximately 80%), but not completely, depleted, and there is a trend for diminished numbers of putative dendritic cells. Neither interstitial dendritic cells nor tissue macrophages in heart are affected. The results at day 7 were very similar to day 2. Substantial depletion of blood monocytes and NK cells might attenuate the innate immune system, and represent a possible supplementary mechanism (in addition to T cell depletion) for suppression of rejection. It might be of particular importance in reducing defences against infections. Monitoring these parameters could be of clinical value.

Connections between attachment styles and relationship patterns are studied on 32 female psychotherapy patients. Our study gives first hints to a connection between attachment variables, assessed by the German version of the Adult Attachment Prototype Rating (AAPR) and predominant relationship patterns, assessed by the Core Conflictual Relationship Theme Method (CCRT) developed by Luborsky, if both methods are used independently. Subsamples according to the attachment styles show differences in CCRT variables.

This study, carried out at three different university centers contributes to validating the valence dimension of the CCRT-method. Working on the state of the CCRT-research on affective evaluation of relationship narratives, the connection between the valence dimension of the responses from others (RO), responses of the self (RS) and the severity of the psychic disorder has been analysed with the help of two different samples (n = 266 resp. n = 32) taken from female patients. Both, therapists as well as patients themselves, evaluated the severity of the impairment similarly. The more the patients were impaired, the more negatively they describes both their own reactions and those of their interaction partners as shown in the relationship episodes.

Well-known arterial complications after liver transplantation comprise thrombosis and major stenosis, which usually necessitate a retransplantation procedure. In our institution, in a series of 165 consecutive liver transplantations, we report the first recognized case of a splenohepatic arterial steal syndrome. This is characterized by an arterial malperfusion of the hepatic graft caused by a marked diversion of blood flow to a significantly enlarged spleen, which leads to major ischemic damage of the hepatic graft. After splenectomy the perfusion through the hepatic artery increased substantially and the graft was salvaged, with a following favorable clinical course. Splenohepatic arterial steal syndrome may ultimately result in graft loss if it is falsely diagnosed or recognized too late. A post-transplantation splenectomy represents a successful therapeutic approach; alternatively a primary arterial anastomosis to the aorta prevents the development of this condition.