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ABSTRACT: Only patients with Model for End-stage Liver Disease (MELD) scores ≥18 or ≥17 experience a survival benefit (SB) at 12 and 36 months after liver transplantation (OLT). The SB calculation estimates the difference after stratification for risk categories between the survival rate of transplanted versus waiting list patients. The aim of this study was to perform a short- and long-term (60 months) SB analyses of a Italian OLT program. One-hundred seventy-one patients were stratified into four MELD classes (6-14, 15-18, 19-25, 26-40), and two groups: namely, waiting list (WL) and transplanted groups (TX). The median waiting time for transplanted patients was 4.4 months (range, 0-35). SB was expressed as mortality hazard ratio (MHR) as obtained through a Cox regression analysis using as a covariate the status of each patient in the waiting list (WL = 0, reference group) or the TX group (TX = 1). Values over 1 indicated the MHR in favor of the WL with the values below 1 indicating MHR in favor of Tx. In the MELD class 6 to 14, the MHR was above 1 at 3 and 6 months, indicating an SB in favor of WL; subsequently, the MHR dropped below 1, indicating an SB in favor of TX (P < .05). In the MELD class 15 to 18 the MHR was above 1 at 3 months, but below 1 subsequently (P < .05). For MELD classes 19 to 25 and 26 to 40, the MHR was always below 1 (P < .01). According to the SB approach, patients in the MELD class 6 to 14 could safely wait for at least 36 months; patients in the MELD class 15 to 18 should likely remain no longer than 12 months on the waiting list, and all the remaining patients with MELD > 18 should be transplanted as soon as possible. OLT should not be precluded but only postponed for MELD < 19 patients.
Transplantation Proceedings 09/2012; 44(7):1851-6. · 1.00 Impact Factor
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A.W. Avolio,
S. Agnes,
M.C. Lirosi,
M. Salizzoni,
A.D. Pinna,
B. Gridelli,
L. De Carlis,
M. Colledan,
G.E. Gerunda,
U. Valente, [......],
T. Manzia,
E. Tondolo,
M. Rendina, M. Barone,
A. Perrella,
M. Romano,
C. De Waure,
P. Burra,
A. Gasbarrini,
U. Cillo
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ABSTRACT: Intentional matching of liver transplant donor-recipient risk factors, supported by D-MELD (donor age null biochemical MELD), could offer a new therapeutic strategy with effects on survival. As yet, an extensive stratification of cases according to the futile transplant principle using a continous quantitative parameter has not been performed. To stratify the prognosis according to donor-recipient match and assess the predictive role of D-MELD together with covariates, a database detailing 5946 liver transplants performed in 21 Italian Centers (2002-2009) was analyzed. Primary endpoint was to evaluate the prognostic power of D-MELD and covariates in terms of 3-year patient survival. The futile-transplant cutoff (life-expectancy <50% at 5 years) was investigated. The database was divided into a training and a validation set. The adequacy of fit for both sets was tested using Hosmer-Lemeshow and C-statistics. Cases were stratified in ten D-MELD deciles. Significant differences among D-MELD deciles allowe
Journal of Hepatology. 01/2011; 54:S17.
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ABSTRACT: Androgen receptors (ARs) act as transcription factors. An increased AR activity could be due either to mutations or to an increased expression of the receptor. AR mutations involving the hormone binding domain could increase AR function and promote carcinogenesis, as suggested for prostate cancer.
Herein, we evaluated qualitative (point mutations involving the hormone binding domain) and quantitative AR alterations and their possible correlation with cell proliferation and tumour grading.
Carcinomatous and non-cancerous surrounding liver tissue was collected from 14 Caucasian patients with hepatocarcinoma. They were all affected by cirrhosis with different aetiologies.
AR missense mutations, AR mRNA and protein levels, AR distribution in the liver, liver cell proliferation, and tumour staging were evaluated by DNA sequencing, quantitative real-time PCR, Western blot analysis, immunofluorescence, PCNA immunostaining, and conventional histological techniques, respectively.
AR gene regions encoding the hormone binding domain did not contain any missense mutation. AR mRNA and protein levels were increased in hepatocarcinoma compared to non-cancerous surrounding tissue. Cell proliferation was significantly increased in the tumour compared to non-cancerous surrounding tissue.
Mutations of the AR regions studied were not involved in hepatocarcinogenesis. Elevated AR levels in transformed cells could have a tumour promoting effect by stimulating cell growth.
Digestive and Liver Disease 03/2009; 41(9):665-70. · 3.05 Impact Factor
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ABSTRACT: Epidemiological data demonstrate that HCC is prevalent in men compared to women. Herein, we examined the effect of gonadectomy in a murine model that spontaneously develops HCC.
Thirty-two male and 26 female HBV transgenic mice [Tg (Alb-1 HBV) Bri 44] underwent surgical castration or sham operation. At the 18th month, serum samples were collected and all mice were sacrificed. Liver weight and volume were evaluated, each liver was cut into 1.5-mm-thick consecutive slices and nodules were examined on freshly isolated tissue. Consecutive histological sections obtained from each liver slice were evaluated to confirm the diagnosis of HCC.
Sham-operated females showed a significantly lower neoplastic growth compared to sham-operated males. This difference disappeared when females underwent gonadectomy. In males, neoplastic growth was not influenced by gonadectomy. Testosterone and estradiol levels were profoundly modified by gonadectomy in both males and females. The testosterone/estradiol ratio in gonadectomized females increased 4.5-fold compared to that in sham-operated females, becoming more similar to the ratio observed in castrated and sham-operated male mice.
HCC growth in our experimental model was not simply influenced by the levels of testosterone or estradiol, taken singularly, but depended on their ratio.
Digestive and Liver Disease 05/2008; 41(2):150-5. · 3.05 Impact Factor
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ABSTRACT: A pivotal role of oestrogen receptor-beta has been suggested in colon carcinogenesis in humans. However, few data are available on oestrogen receptor-beta in colorectal pre-cancerous lesions.
In the present study, we evaluated oestrogen receptor-beta expression and its possible correlation with proliferative activity and apoptosis in colorectal adenomas and normal colon tissue.
Adenomatous tissue from 25 patients with colonic polyps, and normal tissue from 25 controls were used. Oestrogen receptor-beta expression, colonocyte proliferation (expressed as PCNA positivity) and apoptosis were evaluated.
In adenomatous tissue, a significant reduction of oestrogen receptor-beta was observed compared to normal mucosa (10.1+/-5.5% vs. 44.2+/-13.7; p<0.03), while the expression of oestrogen receptor-alpha remained unvaried. Cell proliferative activity significantly increased in adenomatous tissue compared to normal mucosa (59.3+/-7.1 vs. 18.5+/-8.8; p<0.0001), doubling the PCNA/apoptosis ratio. An inverse correlation was found between oestrogen receptor-beta and PCNA expression in adenomas (r=-0.81), a datum confirmed by confocal microscopy evaluation.
Our data demonstrate, for the first time, a significant reduction of oestrogen receptor-beta expression already in the pre-cancerous phase of colon carcinogenesis. This suggests a role of selective oestrogen receptor-beta agonists in the prevention of colorectal cancer.
Digestive and Liver Disease 04/2008; 40(4):260-6. · 3.05 Impact Factor
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ABSTRACT: MELD and PELD scores of 255 consecutive grafts were calculated (236 adult cases and 19 pediatric cases). No correction for the etiology of liver disease was performed. Retransplants were excluded. Three categories of patients were identified: low MELD (scores <12, n = 61); intermediate MELD (scores between 12-24, n = 159); high MELD (scores > or =25, n = 35). Grafts were categorized according to donor quality: standard livers (n = 199), vs nonstandard livers (n = 56). Nonstandard livers were identified by age > or =60, or at least by two of the following conditions: severe hemodynamic instability, ultrasound evidence of steatosis, natriemia > or =155 mEq/L, ICU stay >7 days, liver trauma, protracted anoxia as cause of brain death, transaminases levels x 4. In standard livers, the 12-month graft survival (GS) for low, intermediate, and high MELD classes were 88%, 74%, and 77%, respectively. In nonstandard livers, the 12-month GS for the low, intermediate, and high MELD classes were 84%, 55%, and 44%, respectively; differences between low MELD class and both intermediate and high MELD classes were significant (P < .05). Cox regression analysis of all cases identified the following parameters as independent predictors of GS: donor status; donor age; and recipient creatinine. The highest correlation with GS was found using donor age and recipient creatinine as covariates. In standard livers no variable was able to predict GS. In nonstandard livers the MELD-PELD score was the unique variable able to predict GS. We suggest avoiding the use of nonstandard livers for patients with high MELD scores.
Transplantation Proceedings 12/2006; 38(10):3567-71. · 1.00 Impact Factor
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ABSTRACT: Candidates for liver transplantation with AB blood group remain on the waiting list for shorter times than candidates with O blood group. To investigate the reasons of this phenomenon, we analyzed data concerning deceased donors, liver transplant candidates, and liver first transplants performed in the United States during the period 2003 to 2004. The percentage of deceased donors with blood group O was higher than that of candidates on the waiting list with the identical blood group (P < .05). On the other hand, for blood groups A, B, and AB an opposite situation was observed: the percentages of deceased donors were significantly lower compared to those candidates with the identical blood group (A blood group, P < .05; B and AB blood groups, P < .001). When the number of grafts from deceased donors was compared with the number of those effectively transplanted, a negative difference for O blood group recipients was found (ie, transplanted livers < harvested livers) and a positive one for AB blood group (transplanted livers > harvested livers) were found. Since disease progression and causes of acute liver failure, including primary nonfunction and hepatic artery thrombosis leading to retransplantation were similar among the various blood groups, we concluded that the shorter waiting time for AB patients in the pre-MELD era was due to the use of compatible livers to the detriment of group O recipients.
Transplantation Proceedings 06/2006; 38(4):1063-5. · 1.00 Impact Factor
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ABSTRACT: The purpose of this study was to establish if estrogen-induced hepatocyte proliferation in vitro involves the cell cycle regulators cyclin D1, p21(Cip1), and p27(Kip1). Male rat hepatocytes were cultured in presence of 17-beta-estradiol (E2) +/- ICI-182780, a pure estrogen antagonist, and [3H]-thymidine, as required. DNA synthesis as well as p21(Cip1), p27(Kip1), and cyclin D1mRNA and protein levels were evaluated at different times (12, 24, 36, and 48 hours) of incubation. E2-increased DNA synthesis was correlated with cyclin D1 and p21(Cip1) (mRNA and protein) variations that were reversed by the addition of ICI-182780. p27(Kip1) protein levels progressively increased regardless of the presence of E2 or ICI-182780. Our data confirm that estrogens' stimulatory effect is related to their ability to increase cyclin D1 levels. The increase of p21(Cip1) is probably related to the reentry of hepatocytes in the quiescent state. p27(Kip1) protein is not able to arrest hepatocyte proliferation.
Digestive Diseases and Sciences 04/2006; 51(3):580-6. · 2.12 Impact Factor
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V De Francesco,
A Zullo,
M Margiotta,
S Marangi,
O Burattini,
P Berloco,
F Russo, M Barone,
A Di Leo,
M F Minenna,
V Stoppino,
S Morini,
C Panella,
A Francavilla,
E Ierardi
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ABSTRACT: Predicting factors for the outcome of conventional Helicobacter pylori triple therapy have been identified. Of these, the presence of the CagA gene is a strong predictor of successful treatment. Our preliminary data show that this factor becomes irrelevant when sequential therapy is used.
To identify predicting factors for the outcome of H. pylori eradication using two therapeutic schemes (triple and sequential) of equal duration (10 days).
Ninety-six patients with H. pylori infection were randomly assigned to receive one of the following therapeutic schemes: group A: rabeprazole (20 mg b.d.) plus amoxicillin (1 g b.d.) for 5 days, followed by rabeprazole (20 mg b.d.) plus tinidazole (500 mg b.d.) and clarithromycin (500 mg b.d.) for a further 5 days; group B: rabeprazole (20 mg b.d.) plus amoxicillin (1 g b.d.) and clarithromycin (500 mg b.d.) for 10 days. Age, sex, smoking, endoscopic and histological findings, and CagA and VacA status were considered as candidates for a model of multivariate analysis which used therapeutic outcome as the dependent variable. CagA and VacA status were assessed by polymerase chain reaction on DNA isolated from gastric antral specimens.
The sequential scheme was significantly more effective than prolonged triple therapy (P < 0.05). Smoking (P < 0.001) and the absence of the CagA gene (P < 0.05) were significantly associated with the failure of triple therapy, but the effectiveness of sequential treatment was not predicted by these factors.
Our data suggest that sequential therapy is not affected by bacterial and host factors which have, until now, predicted the outcome of conventional eradication treatments.
Alimentary Pharmacology & Therapeutics 03/2004; 19(4):407-14. · 3.77 Impact Factor
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ABSTRACT: We report two cases of hepatitis C virus (HCV) associated autoimmune haematological disorders successfully treated with an unusual protocol (mycophenolate mofetil: MMF). The first case was a male patient with chronic HCV infection who developed, during interferon (IFN)/ribavirin therapy, severe autoimmune thrombocytopenia unresponsive to steroids. MMF was then administered and, simultaneously, the steroid dose was gradually reduced until withdrawal. Following this strategy, a progressive increase in platelet count and complete negativity of anti-PLT antibodies were achieved without changes in HCV-RNA quantitative determination. The second case was a woman with HCV liver cirrhosis with severe anaemia and Coombs test positivity partially responsive to continuous administration of steroid high doses. However, this treatment unmasked a severely painful vertebral osteoporosis. For this reason we introduced MMF and simultaneously steroid therapy was progressively reduced until withdrawal. Haemoglobin reached a normal value and the Coombs test became negative within 60 days. These case reports suggest that MMF may represent an interesting therapeutic approach for autoimmune HCV associated haematological disorders.
Journal of Viral Hepatitis 10/2003; 10(5):390-3. · 4.09 Impact Factor
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E Ierardi,
A Di Leo, M Barone,
S Marangi,
O Burattini,
A Panarese,
M Margiotta,
R Francavilla,
C Panella,
A Francavilla,
R Cuomo
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ABSTRACT: Helicobacter pylori (HP) related inflammation is mediated by tumour necrosis factor alpha (TNFalpha), which "in vitro" increases epithelial apoptosis in response to infection. In the early stages of HP gastritis, a raised epithelial apoptosis occurs; this phenomenon becomes less evident with progression towards intestinal metaplasia. Aim of our study was to analyze "in vivo" mucosal TNFalpha in relation to epithelial apoptosis in the progression of HP related histological damage. Antral biopsies from 20 HP positive patients were retrospectively studied: 10 with and 10 without intestinal metaplasia (IM and CG group respectively); samples of 10 dyspeptics with normal HP negative stomach (N) were used as control. The following parameters were evaluated by immunohistochemistry: 85 kDa caspase-cleaved fragment (p85) of human poly (ADP-ribose) polymerase (PARP) labelling index (LI) as marker of apoptosis and TNFalpha LI in stromal cells as marker of inflammatory response. Both epithelial apoptosis and mucosal TNFalpha expression were higher in chronic active gastritis compared to intestinal metaplasia and controls (PARP and TNFalpha LI: CG > IM > N; ANOVA & Student-Neumann-Keuls; p < 0.05 and p < 0.01, respectively). Pearson's coefficient showed a significant correlation between PARP and TNFalpha LI in IM and CG groups. Our data show that mucosal TNFalpha, similarly to what suggested "in vitro", may be related "in vivo" to epithelial apoptosis thus suggesting a possible mechanism for immune system involvement in the control of gastric epithelial turnover.
Immunopharmacology and Immunotoxicology 06/2003; 25(2):203-11. · 1.83 Impact Factor
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E Ierardi,
N Muscatiello,
M Nacchiero,
M Gentile,
M Margiotta,
S Marangi,
V De Francesco,
R Francavilla, M Barone,
D Faleo,
C Panella,
A Francavilla,
R Cuomo
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ABSTRACT: Recently, biliary sludge has been strongly correlated with 'idiopathic pancreatitis'. It is often diagnosed by trans-abdominal ultrasonography, despite the low sensitivity of this investigation. New scanners, using second harmonic imaging, may improve the quality of the echographic picture.
To verify the impact of this methodology on the detection of biliary sludge in patients with 'idiopathic' pancreatitis.
Fifty patients with 'idiopathic' pancreatitis observed over a 18-month period entered the study. Exclusion criteria were gall-bladder stones, polyps, clinical conditions related to biliary sludge development and haemolytic disorders. Patients were assessed blind by two operators using either conventional ultrasonography or second harmonic imaging. The parameters of diagnostic quality of both examinations were evaluated using, as the gold standard, microscopic examination of the gall-bladder content collected at endoscopy after cholecystokinin infusion.
An improvement in sensitivity, specificity, efficiency and negative predictive value was obtained by second harmonic imaging compared with conventional ultrasonography.
Second harmonic imaging, in our experience, is a reliable non-invasive tool for the diagnosis and follow-up of biliary sludge in the course of 'idiopathic' pancreatitis.
Alimentary Pharmacology & Therapeutics 03/2003; 17(3):473-7. · 3.77 Impact Factor
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ABSTRACT: Despite the clear demonstration that an increase in faecal bile salt concentration can augment colonocyte proliferation, it is still controversial whether bile salts act on these cells as direct mitogens or by inducing a damage-related proliferative response. The goal of this study was to define the mechanism mediating the proliferative effect of bile salts on rat colonocytes.
Faecal bile salt concentration was increased by feeding rats on diets enriched with either bile salts or fats. Colonic mucosa proliferating cell nuclear antigen (PCNA) expression, histology and apoptosis, and faecal water cytolytic activity were evaluated to assess proliferation and direct or indirect signs of mucosal damage.
Compared to standard diet, chenodeoxycholate-, deoxycholate- and fat-enriched diets produced a significant increase in both faecal water total bile salt concentration (46.0 versus 124.1, 145.9 and 498.5 micromol/L, respectively) and percentage of PCNA-positive nuclei (30.5, versus 37.7, 33.9 and 47.1, respectively) that appeared significantly correlated (r = 0.8; P < 0.001). Chenodeoxycholate and deoxycholate fed animals showed colonic mucosa histology and faecal water cytolytic activity similar to controls, with a significantly reduced apoptotic index. Rats fed on high fat diet, however, showed a mild inflammatory infiltrate associated with an increased apoptosis and faecal water cytolytic activity, all conditions not apparently determined by the increased faecal water total bile salt concentration.
The results obtained in this study demonstrate that bile salts act as direct mitogens on colonic epithelial cells.
Scandinavian Journal of Gastroenterology 01/2002; 37(1):88-94. · 2.02 Impact Factor
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ABSTRACT: A study is presented of the effect of the bile salt ursodeoxycholate (UDC) on protein phosphorylation by [gamma-32P]ATP in the cytosol from rat hepatocytes. Gel electrophoresis and corresponding autoradiograms of cytosolic proteins show that UDC promotes phosphorylation of at least eight different protein bands. Four of them (the 36, 60, 64 and 76 kDa) are phosphorylated by Ca2+ and phospholipid-dependent protein kinase (PKC); three (the 31, 51 and 71 kDa) are phosphorylated by cAMP-dependent protein kinase (PKA) and one protein band, with molecular weight of 34 kDa, apparently contains substrates of both PKC and PKA. Data are reported indicating that UDC can directly affect the intrinsic activity of protein kinases.
Biochemistry and molecular biology international 03/1997; 41(2):329-37.
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ABSTRACT: In this study, the stimulatory effect of bile salts (BS) was evaluated both in vitro, using hepatocyte primary cultures, and in vivo, in normal and 40% partially hepatectomized rats previously fed on BS-enriched diets for 4 weeks. In vitro results show that conjugated cholate (CA) and chenodeoxycholate (CDCA) augmented proliferative activity in rat hepatocytes cultured in absence of mitogens, whereas conjugated deoxycholate (DCA), and ursodeoxycholate (UDCA) did not have any significant effect. None of these BSs increased significantly the replicative response induced by submaximal concentrations of epidermal growth factor (EGF). In vivo, at the end of dietary treatment all animals fed on CA or DCA but not those fed on either CDCA, or UDCA, or tauroursodeoxycholate (TUDCA) developed cholestatic hepatitis and a burst of damage-induced hepatocyte proliferation. After 40% partial hepatectomy (PH), CA- and DCA-treated groups underwent a deterioration of cholestatic hepatitis. On the other hand, in CDCA-, and UDCA-, and TUDCA-treated groups liver histology, serum glutamic pyruvic transaminase (SGPT) and cholestasis indices did not change significantly compared with controls. As far as the proliferative activity, a significant increase was observed not only in CA and DCA but also in UDCA- and TUDCA-fed groups compared with controls, whereas a slight decrease was observed in CDCA-treated animals. In conclusion, our data indicate that conjugated BSs had only a modest stimulatory effect on hepatocyte proliferation in vitro. However, in vivo, in PH rats, UDCA or TUDCA treatment determined a further increase of hepatocellular proliferation not attributable to hepatotoxic effects. Our result suggest that modifications of bile acid pool could modulate hepatocellular proliferation.
Hepatology 06/1996; 23(5):1159-66. · 11.66 Impact Factor
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ABSTRACT: Despite numerous studies on the effects of bile salts therapy in chronic liver disease, there are no reports on the influence such therapy has on hepatocyte proliferation. The aim of this preliminary study was to evaluate the effect of TUDCA on hepatocyte proliferation in 5 patients with HCV-correlated chronic liver disease. All patients were treated with TUDCA (10-13 mg/day) for three months and the determination of PCNA (Proliferating Cell Nuclear Antigen) expression was used to assess the proliferative activity of hepatocytes at the beginning and at the end of treatment. TUDCA reduced both ALT and Knodell's score in the 5 patients in whom a significant increase of PCNA-LI (p < 0.05) was observed after treatment. TUDCA administration seems to stimulate hepatocyte proliferation in man.
The Italian journal of gastroenterology 07/1995; 27(5):256-8.
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ABSTRACT: In this study the influence of sodium ursodeoxycholate (UDC) on hepatocyte replicative activity was evaluated using quiescent or primed hepatocytes obtained from normal rats or from rats fed with a protein-free diet, respectively. At physiological concentrations UDC stimulated proliferation in quiescent or primed hepatocytes cultured in minimum essential medium plus insulin, and augmented the replicative activity in hepatocytes already stimulated by low concentration of epidermal growth factor and normal rat serum. However, UDC was not the only bile salt (BS) to show this stimulatory effect on hepatocyte proliferation. The stimulatory activity of BSs was not correlated with their degree of hydrophilia.
Journal of surgical oncology. Supplement 02/1993; 3:8-13.
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Journal of surgical oncology. Supplement 02/1993; 3:1-7.
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ABSTRACT: It is known that there is a close relationship between cirrhosis and liver cancer. The proliferative phenomena characterizing liver cirrhosis seem to be predisposing factors for carcinoma. In fact, they differ from the self-limiting proliferative phenomena occurring in normal liver regeneration because they are associated with: 1) an abnormal hormonal pattern; 2) an altered arrangement of hepatocytes and non-parenchymal cells within the lobule; 3) an altered production of growth factors able to modulate liver regeneration; and 4) an abnormal oncogene expression. Under such conditions many carcinogens, which require the target cell to be in a replicative phase, have the opportunity to act.
The Italian journal of gastroenterology 01/1992; 23(9):589-93.
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ABSTRACT: Completely diverting portacaval shunt (Eck's fistula) in dogs causes hepatocyte atrophy, disruption of hepatocyte organelles, fatty infiltration and low-grade hyperplasia. The effect of hepatic growth regulatory substances on these changes was assessed by constantly infusing test substances for four postoperative days after Eck's fistula into the detached left protal vein above the shunt. The directly infused left lobes were compared histopathologically with the untreated right lobes. In what has been called an hepatotrophic effect, stimulatory substances prevented the atrophy and increased hepatocyte mitoses. Of the hormones tested, only insulin was strongly hepatotrophic; T3 had a minor effect, and glucagon, prolactin, angiotensin II, vasopressin, norepinephrine and estradiol were inert. Insulin-like growth factor, hepatic stimulatory substance, transforming growth factor-alpha and hepatocyte growth factor (also known as hematopoietin A) were powerfully hepatotrophic, but epidermal growth factor had a barely discernible effect. Transforming growth factor-beta was inhibitory, but tamoxifen, interleukin-1 and interleukin-2 had no effect. The hepatotrophic action of insulin was not altered when the insulin infusate was mixed with transforming growth factor-beta or tamoxifen. These experiments show the importance of in vivo in addition to in vitro testing of putative growth control factors. They illustrate how Eck's fistula model can be used to screen for such substances and possibly to help delineate their mechanisms of action.
Hepatology 11/1991; 14(4 Pt 1):665-70. · 11.66 Impact Factor
