Dearterialization of the liver causes intrahepatic cholestasis due to reduced bile transporter expression

BACKGROUND: Bile duct injury after hepatic artery thrombosis (HAT) in liver transplantation is believed to be caused by ischemia predominantly. We aimed to define the involvement of bile secretory dysfunction in the pathogenesis of liver injury after HAT. METHODS: In a murine model, the main hepatic artery, the extrahepatic peribiliary plexus, or both arterial connections to the liver were interrupted (n=5 for each group). After 1, 14, or 28 days, hepatobiliary function was assessed by analysis of bile transporter expression, serum bile acids and bilirubin, and hepatic ATP content. In addition, cellular injury was assessed by light microscopy and biochemical markers. RESULTS: There were no signs of hepatobiliary dysfunction or injury in sham-operated animals or in mice with interruption of the hepatic artery or the extrahepatic peribiliary plexus alone. However, as early as 24 hr after complete dearterialization, bile transporter expression was significantly reduced and intrahepatic cholestasis started to progress the following weeks. Histologic studies at 28 days after complete dearterialization showed severe hepatobiliary injury. CONCLUSIONS: This study indicates that arterial blood supply is critical for normal bile secretion. Bile duct injury after complete arterial deprivation is preceded by a loss of bile secretory function and subsequent intrahepatic cholestasis.     

Next generation coronary CT angiography: in vitro evaluation of 27 coronary stents

Objectives

To evaluate in-stent lumen visibility of 27 modern and commonly used coronary stents (16 individual stent types, two stents at six different sizes each) utilising a third-generation dual-source CT system.

Methods

Stents were implanted in a plastic tube filled with contrast. Examinations were performed parallel to the system's z-axis for all stents (i.e. 0°) and in an orientation of 90° for stents with a diameter of 3.0 mm. Two stents were evaluated in different diameters (2.25 to 4.0 mm). Examinations were acquired with a collimation of 96?×?0.6 mm, tube voltage of 120 kVp with 340 mAs tube current. Evaluation was performed using a medium-soft (Bv40), a medium-sharp (Bv49) and a sharp (Bv59) convolution kernel optimised for vascular imaging.

Results

Mean visible stent lumen of stents with 3.0 mm diameter ranged from 53.3 % (IQR 48.9???56.7 %) to 73.9 % (66.7???76.7 %), depending on the kernel used at 0°, and was highest at an orientation of 90° with 80.0 % (75.6???82.8 %) using the Bv59 kernel, strength 4. Visible stent lumen declined with decreasing stent size.

Conclusions

Use of third-generation dual-source CT enables stent lumen visibility of up to 80 % in metal stents and 100 % in bioresorbable stents.

Key Points

? Blooming artefacts impair in–stent lumen visibility of coronary stents in CT angiography. ? CT enables stent lumen visibility of up to 80 % in metal stents. ? Stent lumen visibility varies with stent orientation and size. ? CT angiography may be a valid alternative for detecting in-stent restenosis.     

German Association of Endocrine Surgeons practice guideline for the surgical management of malignant thyroid tumors

Introduction

Over the past years, the incidence of thyroid cancer has surged not only in Germany but also in other countries of the Western hemisphere. This surge was first and foremost due to an increase of prognostically favorable (“low risk”) papillary thyroid microcarcinomas, for which limited surgical procedures are often sufficient without loss of oncological benefit. These developments called for an update of the previous practice guideline to detail the surgical treatment options that are available for the various disease entities and tumor stages.

Methods

The present German Association of Endocrine Surgeons practice guideline was developed on the basis of clinical evidence considering current national and international treatment recommendations through a formal expert consensus process in collaboration with the German Societies of General and Visceral Surgery, Endocrinology, Nuclear Medicine, Pathology, Radiooncology, Oncological Hematology, and a German thyroid cancer patient support organization.

Results

The practice guideline for the surgical management of malignant thyroid tumors includes recommendations regarding preoperative workup; classification of locoregional nodes and terminology of surgical procedures; frequency, clinical, and histopathological features of occult and clinically apparent papillary, follicular, poorly differentiated, undifferentiated, and sporadic and hereditary medullary thyroid cancers, thyroid lymphoma and thyroid metastases from primaries outside the thyroid gland; extent of thyroidectomy; extent of lymph node dissection; aerodigestive tract resection; postoperative follow-up and surgery for recurrence and distant metastases.

Conclusion

These evidence-based recommendations for surgical therapy reflect various “treatment corridors” that are best discussed within multidisciplinary teams and the patient considering tumor type, stage, progression, and inherent surgical risk.     

Effects of acarbose on serum lipoproteins in healthy individuals during prolonged administration of a fiber-free formula diet

The effects of the disaccharidase inhibitor acarbose on serum lipoprotein lipid concentrations were investigated in healthy subjects during prolonged feeding of a fiber-free formula diet. Acarbose was shown to decrease cholesterol and fasting triglyceride concentrations, whereas the postprandial increment of triglycerides was not diminished. The response of fasting triglycerides to acarbose treatment appeared to be related to dietary fat intake, but not to the drug-induced reduction of postprandial glucose and insulin concentrations. Both the triglyceride and the cholesterol lowering efficacy were less pronounced with a higher amount of saturated fat than with a lower intake of fat mainly composed of polyunsaturated fatty acids. The decrease in total cholesterol was shown to be a consequence of a significant reduction in low density lipoprotein (LDL) cholesterol. Since high density lipoprotein (HDL) cholesterol concentrations remained unaltered, the ratio of HDL/LDL cholesterol changed in a beneficial way.     

Endovascular brachytherapy in peripheral arteries: Solution for restenosis or false hope?

Opinion statement Endovascular brachytherapy with gamma-radioactive source (¹⁹²iridium [¹⁹²Ir]) significantly reduces the restenosis after femoropopliteal angioplasty for both de novo and recurrent lesions. Increased arterial patency after additional stenting and brachytherapy was also achieved with the same approach. This was found as a result of single-center studies performed in Frankfurt, Germany, Vienna, Austria, and Bern, Switzerland. However, until recently, only one multicenter investigation was published that also underlined this positive effect of brachytherapy. A definitive role of radiotherapy in restenosis prevention should be established after the results of three multicenter, phase III trials (ie, Paris, Vienna-3, and Swiss) are presented in early 2003. These investigations recruited approximately 630 patients with recurrent and de novo lesions without stent placement. Another important phase III study, the results of which are also expected at the beginning of 2003, is the Vienna-5 trial. This study had the same inclusion criteria as the Paris and Vienna-3 trials, but angioplasty was combined in all patients with stenting. The patients were then randomized for brachytherapy or sham irradiation. Endovascular brachytherapy has shown to be a safe treatment modality. The only clinically relevant impediment was the late sudden thrombosis or occlusion that occurred after stenting and radiation. These events can present up to 1 year after brachytherapy, and in some cases even later. Prolonged antiplatelet medication with clopidogrel (at least 12 months) has solved this problem completely. No other major adverse effects were seen. If gamma radiation is used, the patients must be transported after intervention to the brachytherapy suite, owing to radiation safety regulations. Although no negative consequences during transportation were observed in all performed studies, this represents an additional risk. To shorten the whole procedure, studies using beta sources (³²phosphorus, ⁹⁰strontium) are ongoing, whereas those with beta-radioactive sources of brachytherapy can be performed in the catheterization laboratory. Emerging approaches using drug-eluting stents with antiproliferative substances such as rapamycin and paclitaxel are being investigated as well; however, the safety and efficacy for restenosis prophylaxis must be proven in large clinical trials.     

The role of lymphocyte subsets and adhesion molecules in T cell-dependent cytotoxicity mediated by CD3 and CD28 bispecific monoclonal antibodies

The cure of human Hodgkin's tumors heterotransplanted into SCID mice can be achieved by two bispecific monoclonal antibodies (Bi-mAb) directed against the tumor-associated CD30 antigen and CD3 and CD28, respectively, and normal peripheral human blood T cells. We investigated the role of lymphocyte subsets and adhesion molecules in this Bi-mAb-mediated cytolysis. CD4⁺ lymphocytes were the most rapidly expanding subpopulation, but Bi-mAb-directed cytotoxicity was mediated preferentially by CD8⁺ lymphocytes and effector cells belonging to the CD45RO⁺ “memory” pool. Blocking of the LFA-1/ICAM-1 or CD2/LFA-3 adhesion pathways by mAb decreased Bi-mAb-mediated cytotoxicity. This was not due to inhibition of aggregate formation between Bi-mAb-coated T lymphocytes and target cells. Cross-linking of LFA-1 or CD2 molecules on lymphocytes prestimulated with Bi-mAb bound to CD3 and CD28 antigen lead to a more pronounced and prolonged rise in the intracellular concentration of free Ca²⁺. Additional CD2 cross-linking resulted in the tyrosine phosphorylation of distinct proteins. These findings indicate that adhesion molecules play a critical role and function as co-stimulatory signals rather than as cellular contact mediators in CD3 and CD28 Bi-mAb-stimulated T lymphocytes.     

The effect of the apolipoprotein E polymorphism on lipid levels in patients with familial defective apolipoprotein B-100

Summary Serum lipid concentrations of patients with familial defective apolipoprotein B-100 (FDB) show a high interindividual variability although the underlying defect is caused by a single point mutation. On the other hand, several genetic factors modulating serum cholesterol levels are known, such as DNA polymorphisms of the apopolipoprotein B or the apolipoprotein E (apo E) gene. To assess the effect of the apo E polymorphism on serum cholesterol, lipid levels of FDB patients (n=36) were compared with those of a normolipidemic control group (n=272) according to their apo E genotype. For the FDB group mean values of low-density lipoprotein (LDL) cholesterol (mg/dl) were 225.7 ± 53.7 for E3/2 genotype (n = 3), 234.2±48.3 for E3/3 genotype (n=20), and 252.4±73.8 for E4/3 genotype (n=13). Means of triglycerides (mg/dl) were 121.0±21.2, 114.8± 60.7, and 110.0 ± 62.8 for the respective apo E genotypes. The calculated average effect of the apo E alleles on LDL cholesterol levels was –6.0% for allele e2 and +3.7% for e4 relative to the whole FDB group. The effect on triglyceride levels was +7.5% for e2 and –3.6% for e4. The control group showed a similar variation in LDL cholesterol depending on the different apo E genotypes. About 6% of the total variation in LDL cholesterol can be accounted for by the apo E locus in normolipidemic and hypercholesterolemic individuals alike.Abbreviations FDB familial defective apolipoprotein B-100 - apo apolipoprotein - LDL low-density lipoprotein - VLDL very low density lipoprotein - HDL high-density lipoprotein - PCR polymerase chain reaction Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday     

Alternatively spliced tissue factor promotes breast cancer growth in a β1 integrin-dependent manner

Full-length tissue factor (flTF), the coagulation initiator, is overexpressed in breast cancer (BrCa), but associations between flTF expression and clinical outcome remain controversial. It is currently not known whether the soluble alternatively spliced TF form (asTF) is expressed in BrCa or impacts BrCa progression. We are unique in reporting that asTF, but not flTF, strongly associates with both tumor size and grade, and induces BrCa cell proliferation by binding to β1 integrins. asTF promotes oncogenic gene expression, anchorage-independent growth, and strongly up-regulates tumor expansion in a luminal BrCa model. In basal BrCa cells that constitutively express both TF isoforms, asTF blockade reduces tumor growth and proliferation in vivo. We propose that asTF plays a major role in BrCa progression acting as an autocrine factor that promotes tumor progression. Targeting asTF may comprise a previously unexplored therapeutic strategy in BrCa that stems tumor growth, yet does not impair normal hemostasis.     

Effects of a Warning Signal on Reactions to Aversive White Noise Stimulation: Does Warning “Short-Circuit’ Habituation?

Reduced autonomic and subjective reactions to aversive stimuli under predictable as compared to unpredictable conditions have been explained on the one hand by the mechanism of preception and on the other hand by orienting response (OR) reinstatement in the unpredictable condition, with differences in rated aversiveness not necessarily being involved. To test differential predictions based on an habituation vs. preception position, as suggested by Lykken and Tellegen, one group of male volunteers was presented with 30 trials in which the onset time of an aversive white noise tone (110dBA) was signalled, while in the other group the onset time was not signalled. A control group received unsignalled presentations of 70dBA white noise tones. Following each trial, subjects indicated the aversiveness of the white noise at its impact. SCRs were recorded continuously. Responses produced by the signalled tones decreased over trials, while responses produced by the unsignalled 110dBA tones increased over trials. The control group exhibited a continuous decrease. Self-report measures showed an overall decrease over trials but no differential decline. It was concluded that an OR reinstatement interpretation seems to be best in line with the data, although the observed functional significance of signalling at the autonomic level needs further evaluation to arrive at a clear distinction between OR theory and the preception hypothesis.     

Disturbances in the hypothalamo-pituitary-adrenal and other neuroendocrine axes in bulimia

Disturbances in the hypothalamo-pituitary-adrenal (HPA) and other endocrine axes were assessed in 24 women with bulimia and healthy controls. Overnight blood samples for measuring nocturnal plasma cortisol, prolactin (PRL), growth hormone (GH), luteinizing hormone (LH), and follicle stimulating hormone (FSH) were obtained at 30-min intervals. A 1.5 mg dexamethasone suppression test (DST) and a TRH-test were performed. Patients were monitored closely while their nutritional intake was recorded over 21 days. Compared with healthy controls, nocturnal cortisol plasma levels were not elevated in the bulimics. There was a trend toward insufficient cortisol suppression in the DST in patients with bulimia, which was most pronounced in patients with signs of restricted caloric intake. Plasma dexamethasone levels were significantly reduced in bulimics compared with healthy controls. There was a trend for blunted thyrotropin stimulating hormone (TSH) responses to thyrotropin releasing hormone (TRH) in bulimia. The prolactin response to TRH was significantly reduced in bulimics with a history of anorexia nervosa. Plasma LH and plasma FSH were significantly reduced in bulimics with signs of reduced caloric intake [low T3, high levels of beta-hydroxy-butyric acid (BHBA), reduced daily caloric intake, high number of fasting days] as compared with healthy controls. Bulimics with high BHBA levels had significantly reduced nocturnal prolactin plasma levels. Results show that multiple neuroendocrine disturbances exist in bulimia in a milder form than in anorexia nervosa. Evidence for the impact of caloric intake on endocrine functions is presented. Endocrine dysfunctions in our bulimic sample did not show a positive association with the presence of depressive symptoms.