Portacaval shunt causes apoptosis and liver atrophy in rats despite increases in endogenous levels of major hepatic growth factors

BACKGROUND/AIMS: The response to the liver damage caused by portacaval shunt (PCS) is characterized by low-grade hyperplasia and atrophy. To clarify mechanisms of this dissociation, we correlated the expression of 'hepatotrophic factors' and the antihepatotrophic and proapoptotic peptide, transforming growth factor (TGF)-beta, with the pathologic changes caused by PCS in rats. METHODS: PCS was created by side-to-side anastomosis between the portal vein and inferior vena cava, with ligation of the hilar portal vein. Hepatic growth mediators were measured to 2 months. RESULTS: The decrease in the liver/body weight ratio during the first 7 days which stabilized by day 15, corresponded to parenchymal cell apoptosis and increases in hepatic TGF-beta concentration that peaked at 1.4 x baseline at 15 days before returning to control levels by day 30. Variable increases in the concentrations of growth promoters (hepatocyte growth factor, TGF-alpha and augmenter of liver regeneration) also occurred during the period of hepatocellular apoptosis. CONCLUSIONS: The development of hepatic atrophy was associated with changes in TGF-beta concentration, and occurred despite increased expression of multiple putative growth promoters. The findings suggest that apoptosis set in motion by TGF-beta constrains the amount of hepatocyte proliferation independently from control of liver volume.     

Activation of factor XI in plasma is dependent on factor XII [see comments]

The activation of factor XI initiates the intrinsic coagulation pathway. Until recently it was believed that the main activator of factor XI is factor XIIa in conjunction with the cofactor high molecular weight kininogen on a negatively charged surface. Two recent reports have presented evidence that in a purified system factor XI is activatable by thrombin together with the soluble polyanion dextran sulfate. To assess the physiological relevance of these findings we studied the activation of factor XI in normal and factor XII-deficient plasma. We used either kaolin/cephalin or dextran sulfate as a surface for the intrinsic coagulation pathway, tissue factor to generate thrombin via the extrinsic pathway, or the addition of alpha-thrombin directly. 125I-factor XI, added to factor XI-deficient plasma at physiologic concentrations (35 nmol/L), is rapidly cleaved on incubation with kaolin. The kinetics appear to be exponential with half the maximum cleavage at 5 minutes. Similar kinetics of factor XI cleavage are seen when 40 nmol/L factor XIIa (equal to 10% of factor XII activation) is added to factor XII-deficient plasma if an activating surface is provided. Tissue factor (1:500) added to plasma did not induce cleavage of factor XI during a 90-minute incubation, although fibrin formation within 30 seconds indicated that thrombin was generated via the extrinsic pathway. Adding 1 mumol/L alpha-thrombin (equivalent to 50% prothrombin activation) directly to factor XII deficient or normal plasma (with or without kaolin/cephalin/Ca2+ or dextran sulfate) led to instantaneous fibrinogen cleavage, but again no cleavage of factor XI was observable. We conclude that in plasma surroundings factor XI is not activated by thrombin, and that proposals of thrombin initiation of the intrinsic coagulation cascade are not supportable.     

Target control infusion of propofol: is this method really preferable?

In order to elucidate the advantages of target control infusion (TCI) over common manually controlled infusion, we evaluated the results of 54 anesthesias carried out at department of roentgeno-endovascular surgery. All 54 patients received intravenous controlled sedation with propofol. The rate of arrest of sedation signs after the end of infusion, hemodynamics during anesthesia, comfort for the patient, and convenience for the anesthesiologist were evaluated. As regards intravenous controlled sedation, we observed no obvious advantages of the TCI method for the patient over common manually controlled infusion. Performed by a skilled anesthesiologist, both methods ensure sufficient comfort for the patient, stable hemodynamics, and easy regulation of the depth of sedation. However, TCI is more convenient for physician, and this is the reason why many specialists prefer it.     

A 17-year-old with rash, fever, myalgias, and nephritis

Patients on hemodialysis are at increased risk for developing active tuberculosis (TB) after primary infection. Although this increased risk is well documented, the prevalence of TB infection, as indicated by a positive tuberculin skin test (TST), is not well described. End-stage renal disease is also known to be a risk factor for skin test anergy, but the rate of anergy in hemodialysis patients is unclear. We sought to identify rates of anergy and TST positivity in patients at four hemodialysis units in St Louis, Missouri, from June 1996 through August 1996. Data obtained from patients and medical records included age, years on hemodialysis, medical history, and basic laboratory data. Patients without a history of TB or a positive TST had a TST with Tubersol, as well as candida and tetanus controls, placed by the Mantoux method. Tests were read 48 hours later. Of the patients enrolled at these units, 307 of 331 (93%) were evaluated. Patients had a mean age of 58 years (range, 19 to 91 years) and had been on hemodialysis for a mean of 3.7 years (range, 1 week to 18.7 years). Blacks made up 81% of the population. A history of a positive TST was obtained from 24 patients (8%), and an additional seven (2%) had a history of active TB. Of the 276 patients tested, 93 did not respond to either control antigen, but five of these patients had a positive TST, leaving 88 (32%) anergic. Anergy was related to age, immunosuppressive drug use, and the reagents used, but not to urea reduction ratio. Positive TSTs were found in 17 of 188 of nonanergic patients (9%) (6% of all tested patients). Overall, 48 of 307 patients (16%) had a positive TST or history of TB. TB or a positive TST was associated with liver disease and peptic ulcer disease, but not socioeconomic status. All 17 newly identified TST-positive patients received chest radiographs. No new cases of active TB were found. Only two of 17 of these patients (12%) were started on isoniazid (INH) prophylaxis. We identified high rates of TST positivity and anergy in the hemodialysis patients tested. Hemodialysis patients should receive regular TST screening, and INH prophylaxis needs to be more strongly encouraged. Studies are ongoing to define the rate of TST conversion over time.     

Liver plasma membrane-associated fibroblast growth: stimulatory and inhibitory activities during experimental cirrhosis.

During experimental CCl4 cirrhosis, an increase of membrane-associated factor stimulating 3T3 cell proliferation in vitro was observed. This stimulator is a 150-kD protein similar to one previously described. In situ perfusion released growth stimulatory activity, suggesting a peripheral plasma membrane protein localizing on basolateral surfaces. The activity increased with increasing number of CCl4 treatments, reaching a maximum at the 14th intoxication. It was faster than the proliferation of connective tissues determined histologically. Cessation of treatment caused a decrease in activity to that of the level of untreated liver, although the number of fibroblastlike cells remained large. This data, taken with the results of experiments with enriched hepatocyte fraction, may serve as an evidence in favor of hepatocyte origin of the factor. A factor inhibiting fibroblast proliferation was measured in detergent extracts from membranes, suggesting an integral membrane protein. The activity of the inhibitory factor increased in acute liver lesions, but at the stage of maximal fibrogenesis this factor is reduced to levels comparable to those of the intact liver. Therefore it is unlikely that this factor is involved in CCl4-induced fibrogenesis at the final stages. These factors may be common controls for various hepatic lesions causing fibrosis, both in clinical and experimental modeling.