Plasma levels of soluble urokinase plasminogen activator receptor (suPAR) and high-sensitivity C-reactive protein after Roux-en-Y gastric bypass or sleeve gastrectomy: a 1-year prospective observational study.

PURPOSE: Low-grade inflammation in obesity contributes to the development of cardiovascular disease, diabetes mellitus and cancer, and is associated with increased mortality. The purpose of this 1-year prospective observational study was to examine the weight loss effect of bariatric surgery on plasma concentrations of two inflammatory markers, namely high-sensitivity C-reactive protein (hsCRP) and soluble urokinase-type plasminogen activator receptor (suPAR), in patients with obesity. METHODS: Sixteen subjects without obesity and 32 patients with obesity class III, who had already settled upon Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) were included in the study. Subjects without obesity were examined once, at baseline; patients with obesity were examined preoperatively (baseline) and 3, 6 and 12 months postoperatively. RESULTS: Plasma suPAR and hsCRP concentrations at baseline were higher in patients with obesity than in lean participants (2.68 ± 0.86 vs 1.86 ± 0.34 ng/mL, p < 0.001 and 9.83 ± 9.55 vs 1.36 ± 1.95 mg/dL, p < 0.001). Levels of suPAR following bariatric surgery increased significantly 3 months after either RYGB or SG (3.58 ± 1.58 vs 3.26 ± 0.7 ng/mL, respectively) and declined at 6 (3.19 ± 1.75 vs 2.8 ± 0.84 ng/mL, respectively) and 12 months (2.6 ± 1.5 vs 2.22 ± 0.49 ng/mL, respectively; p < 0.05 for the effect of time on suPAR levels during the study), whereas those of hsCRP declined consistently after bariatric surgery (3 months: 5.44 ± 3.99 vs 9.47 ± 11.98 mg/dL, respectively; 6 months; 5.39 ± 5.6 vs 10.25 ± 17.22 mg/dL, respectively; and 12 months: 2.23 ± 2.5 vs 3.07 ± 3.63 mg/dL, respectively; p < 0.001 for the effect of time on hsCRP levels during the study). 1-year change in BMI was negatively associated with suPAR levels at 12 months. CONCLUSION: Our findings support an association between obesity and low-grade inflammation. Weight loss following bariatric surgery is associated with a consistent decline in plasma hsCRP, while plasma suPAR levels increase at 3 months and decline by 12 months.

Associations between circulating N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) and adiponectin concentrations depend on obesity level in female adolescents: gender dimorphic findings.

N-terminal pro-Brain Natriuretic Peptide (NT-proBNP) is an established biomarker for heart failure in adults, while its plasma concentrations are altered in adult obesity. Plasma adiponectin concentrations are decreased in obesity and low levels are associated with disorders with an increased cardiometabolic risk. A few studies support an association between these two markers in adults with coronary heart disease. Such relations have not been investigated in children with obesity, which is the most prevalent risk factor for cardiovascular disease. Ninety-six children, 24 obese/25 normal BMI boys, and 23 obese/24 normal BMI girls, aged 10-16, were studied. Plasma NT-proBNP was measured using electrochemiluminescence, and adiponectin and other metabolic risk factors, such as glucose, insulin, cholesterol, triglycerides (TG), HDL, and LDL using standard methodology. The findings were gender dimorphic. In overweight and obese females (mean BMI z-score: 2.65+/-1.69), plasma NT-proBNP concentrations correlated significantly with adiponectin levels (r=0.4, r(2)=0.05, p=0.013), while in those with obesity defined as BMI z-score >2.5 (mean BMI z-score: 3.67+/-1.08, n=20) this association was stronger (r=0.6, r(2)=0.22, p=0.005). Adiponectin also correlated significantly with BMI z-scores, TG, HDL, and insulin levels. In boys, there was no correlation between NT-proBNP and adiponectin. NT-proBNP correlated significantly with HDL, while adiponectin correlated with TG, fasting insulin, and the Homeostasis Assessment Model (HOMA) Index. The positive association between NT-proBNP and adiponectin depends on the severity of obesity and is gender dimorphic. This positive correlation in females might be a potential protective mechanism against atherosclerosis in later life.

The immediate and long-term impact of physical and/or emotional stress from motor vehicle accidents on circulating stress hormones and adipo-cytokines in children and adolescents.

Motor vehicle accidents (MVA) represent a complex physical and emotional stressor. Consequent short- and/or long-term alterations on the circulating concentrations of stress hormones and adipo-cytokines may have potential health implications. Fifty-nine children and adolescents, aged 7-18 years, were evaluated within 24 h after hospitalization for a MVA, and 1 and 6 months later; 40 children served as controls. We examined longitudinally the effects of physical injury-associated (PI) group vs. emotional-only stress (ES) group on circulating cortisol, catecholamine, interleukin (IL)-6, leptin and adiponectin concentrations. Within 24 h after the accident, serum cortisol concentration was greater than the controls in the PI but not the ES group (p = 0.02), while serum IL-6 concentration was greater in both trauma groups than in the controls (p = 0.004 for PI, p = 0.04 for ES). Adiponectin concentration was lower in the PI than the ES (p = 0.031) and the control (p = 0.019) groups and this was mainly attributed to females. The catecholamine and leptin concentrations were similar in the three groups. At the 1 and 6 month evaluations, cortisol and IL-6 concentrations in both trauma groups became normal. Adiponectin concentration in females, however, remained low 1 and 6 months after the accident (p = 0.03 for month six). In conclusion, circulating IL-6 concentration was influenced equally by the physical and emotional stress shortly after the trauma. Physical but not emotional-only stress lowered the circulating adiponectin concentrations in females and this effect persisted for at least 6 months.

Low free plasma levels of retinol-binding protein 4 in insulin-resistant subjects with polycystic ovary syndrome.

BACKGROUND: It has been shown in animals and in humans that retinol-binding protein 4 (RBP4) production from adipose tissue leads to generalized insulin resistance (IR). A more sensitive marker of circulating RBP4 is free plasma RBP4 expressed by RBP4 to transthyretin (TTR) ratio, since in circulation RBP4 is bound to TTR. AIM: To investigate RBP4 levels in insulin-resistant women with polycystic ovary syndrome (PCOS) and to estimate free plasma RBP4 expressed by RBP4/TTR ratio. SUBJECTS AND METHODS: Thirty-five PCOS subjects were compared with 45 controls matched for age and body mass index (BMI). In each subject, fasting values of glucose, insulin, gonadotropins, estradiol, androgens, C-reactive protein (CRP), RBP4, and TTR were determined. RESULTS: PCOS subjects in comparison to controls were more insulin-resistant [homeostasis model assessment for IR (HOMA-IR): 2.6+/-0.3 vs 1.9+/-0.1, p=0.043], and presented lower RBP4 levels (28.3+/-1.1 vs 32.4+/-1.2 microg/ml, p=0.021) and RBP4/TTR ratio (0.26+/-0.01 vs 0.31+/-0.01, p=0.0014). When RBP4 and RBP4/TTR values where stratified according to BMI status (obese, overweight, and lean subjects), it was noticed that both RBP4 and RBP4/TTR values in lean PCOS were significantly lower than in controls (RBP4: 25.0+/-5.5 vs 34.1+/-9.0 microg/ml, p=0.0063, RBP4/TTR: 0.25+/-0.3 vs 0.35+/-0.1, p=0.016). No correlation was observed between RBP4 and RBP4/TTR with any hormonal or metabolic parameter including BMI. CONCLUSIONS: RBP4 and free plasma RBP4 expressed as RBP4/TTR ratio are statistically and significantly lower in insulin-resistant PCOS subjects in comparison to controls. Therefore, our findings do not confirm a link between IR, neither with RBP4 nor with free plasma RBP4 levels. The significance of these findings remains to be elucidated, since RBP4 might prove to have different actions, like other adipokines, from humans and rodents.

Peroxisome proliferator activated receptor-gamma ligands as potent antineoplastic agents.

The Peroxisome Proliferator Activated Receptors (PPARs) are initially described as molecular targets for compounds inducing peroxisome proliferation. Among the three PPAR subtypes (alpha, beta, gamma), PPAR-gamma acting as a ligand-activated transcription factor, proved to be an important regulator of adipogenic differentiation and glucose homeostasis. Recent data support evidence for participation of PPAR-gamma, upon ligands activation, in the biological mechanisms underlying the carcinogenic evolution. Specific PPAR-gamma ligands affect cancer cells proliferation and differentiation acting as cell cycle modulators, suggesting their use as an important tool for future therapeutic approach in cancer. In this review, the latest knowledge on PPAR-gamma activation and molecular mechanisms of PPAR-gamma ligands mediated anti-tumoral activity are presented. In vitro and in vivo studies concerning the use of PPAR-gamma ligands in different cancer types are also included.

Effect of cadmium on liver regeneration after partial hepatectomy in rats.

Cadmium is a nonabundant element that is widely distributed throughout the biosphere and its toxic effects are becoming potentially more serious due to industrialization. It has been reported that cadmium might interact with nucleic acid biosynthesis. In this study we examined the effect of cadmium administration, either 24 hr before or simultaneously to partial hepatectomy, on the liver regenerative process in rats, at different time intervals. The rate of DNA synthesis was suppressed markedly in the cadmium pretreated group and the first peak of liver regeneration was delayed, compared to the simply partially hepatectomized one. The administration of cadmium simultaneously to partial hepatectomy, caused a marked decrease of the rate of DNA biosynthesis, compared to the pretreatment. The rate-determining enzyme thymidine kinase was suppressed in the liver of both cadmium-treated groups. Biochemical parameters and histological findings were also coestimated. The above data suggest that either pre- or simultaneous administration of cadmium, suppressed the liver regenerative process, probably due to the inhibition of thymidine kinase.

Induction of metallothionein in the liver of carbon tetrachloride intoxicated rats: an immunohistochemical study.

Metallothioneins (MTs), are low molecular weight proteins, mainly implicated in metal ion detoxification. In the present study, we investigated the expression of hepatic MT in a rat model of injury and regeneration, induced by carbon tetrachloride (CCl(4)) administration. A single intraperitoneal injection of 1 ml CCl(4)/kg body weight was performed in male Wistar rats, killed at different time points post-administration. The enzymatic activities of aspartate and alanine aminotransferases in serum were determined, in addition to the liver histological findings, to estimate hepatotoxicity. The rate of tritiated thymidine incorporation into hepatic DNA, the enzymatic activity of thymidine kinase in liver tissue and the assessment of the mitotic index in hepatocytes, were used as indices of regeneration. MT was detected immunohistochemically in liver tissue sections. CCl(4) administration caused severe hepatic injury, followed by regeneration. MT expression became prominent as early as 12 h after the administration of CCl(4), in the nuclei of hepatocytes, while at 24 and 36 h intense cytoplasmic staining for MT appeared in the hepatocytes in the vicinity of necrotic areas. The peak of hepatocyte proliferative capacity, occurring at 48 h post-CCl(4) administration coincides with the maximum nuclear and cytoplasmic MT expression. At further time points MT expression presented a decreasing trend. Induction of MT expression was observed in the liver after a single administration of CCl(4), being more prominent at the time of maximum hepatocellular proliferation, participating actively in the replication of hepatocytes.

Metallothionein: a multifunctional protein from toxicity to cancer.

The metallothionein (MT) family is a class of low molecular weight, intracellular and cysteine-rich proteins presenting high affinity for metal ions. Although the members of this family were discovered nearly 40 years ago, their functional significance remains obscure. Four major MT isoforms, MT-1, MT-2, MT-3 and MT-4, have been identified in mammals. MTs are involved in many pathophysiological processes such as metal ion homeostasis and detoxification, protection against oxidative damage, cell proliferation and apoptosis, chemoresistance and radiotherapy resistance. MT isoforms have been shown to be involved in several aspects of the carcinogenic process, cancer development and progression. MT expression has been implicated as a transient response to any form of stress or injury providing cytoprotective action. Although MT participates in the carcinogenic process, its use as a potential marker of tumor differentiation or cell proliferation, or as a predictor of poor prognosis remains unclear. In the present review the involvement of MT in defense mechanisms to toxicity and in carcinogenicity is discussed.

Granulocyte colony-stimulating factor administration reverses cadmium-associated inhibition of hepatocyte regeneration.

OBJECTIVE: To document whether the administration of granulocyte colony-stimulating factor (G-CSF) enhances the impaired regenerative response of hepatocytes to partial hepatectomy (PH), in cadmium-pretreated partially hepatectomized rats. MATERIALS AND METHODS: Rats were injected intraperioneally with 2.5 mg CdCl2/kg body weight, 24h before PH. G-CSF (1500 or 150 micrograms/kg body weight) or saline was administered intraperitoneally in cadmium-pretreated partially hepatectomized rats at the same time as PH. The liver regenerative process was estimated 24h after PH. [3H] thymidine incorporation into liver DNA, liver thymidine kinase (TK) activity, mitotic index and proliferating cell nuclear antigen (PCNA) immunostaining were used as indices of hepatocyte proliferation. RESULTS: G-CSF administration in cadmium-pretreated partially hepatectomized rats restored the suppressed DNA biosynthesis and TK activity (P < 0.001), to levels similar to those found in rats that were partially hepatectomized only. The mitotic index and the percentage of PCNA positive nuclei in hepatocytes were also enhanced in G-CSF administered cadmium-pretreated partially hepatectomized groups of rats. CONCLUSION: The administration of G-CSF triggers events that restore the impaired liver regeneration in this model of reduced hepatocyte proliferation.

Liver thymidine kinase activity after cadmium-induced hepatotoxicity in rats.

Intraperitoneal (i.p.) administration of a cadmium (Cd) salt at concentrations of 1.0, 2.5 and 4.0 mg CdCl2/kg body wt. caused severe liver injury in rats 24 h after administration. The toxic effects were most evident in the intermediate dose of 2.5 mg. Thymidine kinase (TK), the key enzyme of the salvage pathway of DNA biosynthesis, was affected in all Cd-treated groups. TK activity presented lower values at the highest Cd-induced hepatotoxicity.

Thymidine kinase activity in liver and serum of rats after cadmium administration.

Intraperitoneal administration of a cadmium (Cd) salt at concentrations of 2.5 and 4.0 mg CdCl2/kg of body wt., caused time-dependent severe liver injury, in Quinster rats, more intense at the higher administered dose. Thymidine kinase, the key enzyme of the salvage pathway of DNA biosynthesis, was strongly affected in liver tissue and serum of cadmium-intoxicated rats. Lower thymidine kinase activity was observed both in liver and serum of rats treated with the higher dose of cadmium, in which the maximal liver injury appeared.

Cadmium-induced hepatotoxicity in three different rat strains.

Cadmium (Cd) is a highly toxic element able to induce acute liver injury in rats after intraperitoneal administration. The dose-dependent Cd-induced hepatotoxicity was examined in three different rat strains. A difference in hepatotoxicity was observed in the three rat strains, determined by the examination of serum enzymes' activities and other biochemical parameters, all markedly altered after Cd intoxication. The histological findings came to confirm the variations of the above-mentioned parameters. It is concluded that the administration of this toxic agent caused different toxicity in the three rat strains examined, indicating a more intense damage in Wistar than in Quinster and Lewis rats.

Liver metallothionein expression in thioacetamide-intoxicated rats.

Metallothioneins (MT), a group of ubiquitous low molecular weight proteins, implicated primarily in metal ion detoxification, are known to be expressed during hepatocellular proliferation after partial hepatectomy in rats. In the present study, we investigated the expression of MT in a rat model of liver injury and regeneration, induced by intraperitoneal administration of thioacetamide (TAA). The animals were killed at 0, 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120 hours after TAA administration. The rate of tritiated thymidine incorporation into hepatic DNA, the enzymatic activity of thymidine kinase, and the assessment of the mitotic index in hepatocytes were used as indices of liver regeneration. Liver MTs were detected immunohistochemically. TAA administration caused severe hepatic injury, followed by regeneration. MT expression became prominent in hepatocytes as early as 12 hours post-TAA administration. At 24 and 36 hours post-TAA administration intense nuclear and cytoplasmic staining of hepatocytes was found in the vicinity of necrotic areas. The maximal nuclear and cytoplasmic MT expression coincides with the peak of hepatocyte proliferative capacity, occurring at 48 and 60 hours post-TAA administration. MT expression correlated positively with the Zn content of liver tissue, but negatively with serum one, at the time of maximum hepatocyte proliferative capacity. This study suggests that MT participates in hepatocyte replication after toxin-induced liver injury.

Retinol Binding Protein 4 in children with Inflammatory Bowel Disease: a negative correlation with the disease activity.

OBJECTIVES: Retinol Binding Protein-4 (RBP-4), the action of which was initially thought to be only the transport of vitamin A, is a major circulating adipocytokine involved in the inflammation. We evaluated the serum RBP-4 levels in children with inflammatory bowel disease (IBD) and correlated them with transthyretin (TTR), inflammation markers, disease activity, and body mass index (BMI). DESIGN: In 41 children of mean age 11.9 ± 3.6 years (range 5-17.7 y) with IBD (19 with Crohn's disease (CD) and 22 with Ulcerative colitis (UC) serum RBP-4, TTR, Amyloid A (SAA), C-Reactive Protein (CRP), Erythrocyte Sedimentation Rate (ESR), disease activity and BMI were prospectively determined and compared with those of 42 matched controls. RESULTS: No difference in the RBP-4 and TTR serum levels, between patients and controls as well as between active and remission state of the disease was noticed. A negative correlation of serum RBP-4 with the disease activity, SAA and ESR and a positive correlation with TTR was found, but no significant correlation with CRP or BMI was found. Inflammation markers were significantly increased in patients compared to controls and had a positive correlation with the disease activity. CONCLUSIONS: RBP-4 negatively correlated with disease activity of children with IBD probably indicating a protective anti-inflammatory mechanism of action in addition to transport of vitamin A.

Effects of mode of delivery on maternal-neonatal plasma antioxidant status and on protein S100B serum concentrations.

OBJECTIVE: To investigate the effect of the mode of labour and delivery on total antioxidant status (TAS) and on the protein S100B serum concentrations in mothers and their newborns. MATERIAL AND METHODS: Sixty women with normal pregnancies were divided into three groups: Group A (n = 20) with normal labour and vaginal delivery (VG), group B (n = 18) with prolonged labour+VG and group C (n = 22) with scheduled caesarean section (CS). Blood was obtained at the beginning of the labour process and immediately after delivery (pre- and post-delivery) as well as from the umbilical cord (CB). TAS and creatine kinase (CK) were measured using commercial kits. Serum S100B levels were evaluated with the electrochemiluminescence immunoassay "ECLIA" on the ROCHE ELECSYS 2010 immunoassay analyser. RESULTS: Post-delivery, TAS levels were significantly decreased in group A and especially in group B. S100B levels were increased in group B (0.0712+/-0.02 microg/L) as compared with those of group A (0.0567+/-0.03 microg/L, p<0.01) and group C (0.038+/-0.03 microg/L, p<0.01), the levels in group C remaining practically unaltered (pre- versus post-delivery). In the newborns, S100B levels were almost 2-fold higher in group B (0.67+/-0.18 microg/L) than those in group A (0.40+/-0.05 microg/L p<0.001) and group C (0.31+/-0.04 microg/L p<0.001). A negative correlation was found between TAS and S100B protein (r = -0.61, p<0.001), the latter positively correlated to CK (r = 0.48, p<0.01). CONCLUSIONS: The increased S100B serum levels in the mothers of group B, post-delivery, may have been due to the long-lasting, oxidative and/or psychogenic stress. The observed remarkably high levels of S100B in the group B newborns may have been due to compressive conditions on the foetus brain during this mode of delivery.

Early markers of renal dysfunction in patients with sickle cell/beta-thalassemia.

Progressive renal failure is one of the main complications in HbS/beta-thalassemia (HbS/beta-thal). Early identification of patients at high risk of developing renal failure is of great importance as it may allow specific measures to delay the progression of renal damage and thus reduce the incidence of end-stage renal failure and mortality. Early predictors of renal impairment in HbS/beta-thal remain to explore. Within this context, we studied 87 compound HbS/beta-thal patients (36 males/51 females; median age 39 years) and 30 healthy controls. In addition to conventional renal biochemistries we measured serum cystatin-C (Cys-C), urine N-acetyl-beta-D-glucosaminidase (NAG) excretion and serum and urinary beta(2)-microglobulin (beta(2)-M). Cystatin-C, NAG and serum beta(2)-M levels were higher in patients than controls. The incidence of patients with high levels of Cys-C, NAG, and beta(2)-M was 32.1, 74.7, and 70.1% respectively, while only 6.8% of patients had increased serum creatinine levels. Cystatin-C and serum beta(2)-M showed a strong correlation with creatinine clearance and age, while NAG positively correlated with proteinuria. An inverse correlation was also shown between hemoglobin and beta(2)-M, NAG, and Cys-C levels. Seven patients with proteinuria received therapy with angiotensin-converting enzyme (ACE) inhibitors. Changes of poteinuria positively correlated with NAG levels. These results indicate that Cys-C is an accurate marker of renal dysfunction, and urinary NAG excretion can be considered as a reliable index of the tubular toxicity, and possible predictor of proteinuria and eventual renal impairment in HbS/beta-thal patients. Furthermore, NAG measurement may be used for monitoring ACE-inhibitors therapy in HbS/beta-thal patients with proteinuria.

Effects of various metals on DNA synthesis and lymphokines production by human peripheral blood lymphocytes in vitro.

1. The presence of Cd2+, Ni2+, Cu2+, Mn2+ and Co2+ (10(-4)-10(-6) M) caused a dose-dependent inhibition of DNA synthesis in phytohemagglutinin (PHA) stimulated peripheral blood mononuclear cells (PBMC) from normal human donors. No inhibition of DNA synthesis was observed in the presence of Mg2+ and Al3+. 2. Spontaneous and PHA induced interleukin-1 (IL-1) was enhanced in the presence of Mn2+. 3. The release of interleukin-2 (IL-2) and soluble interleukin-2 receptors (sIL-2R) was decreased by Cd2+, Cu2+ and Mn2+. 4. Spontaneous tumor necrosis factor-alpha (TNF-alpha) production was enhanced by Co2+ and Al3+, but decreased by Cd2+. 5. gamma-Interferon (gamma-IFN) production was decreased in the presence of Cd2+ and Cu2+ and increased in the presence of Al3+.

Peroxisome proliferator activated receptor-gamma (PPAR-gamma) ligands and angiogenesis.

The peroxisome proliferator activated receptor (PPAR)- gamma ligands have been initially described as important regulators of adipogenic differentiation and glucose homeostasis. Detailed studies in different tissues pointed to the roles of these ligands in cell proliferation and cancer, establishing their anticancer properties against a wide variety of neoplastic cells. The growth of any solid tumor depends on angiogenesis, as tumor vascularization is a vital process for tumor volume increase and its metastatic potential. Recently, the role of PPAR- gamma ligands as potent angiogenesis modulators in vitro and in vivo, has been referred. This review takes into consideration the latest data concerning the participation of PPAR- gamma ligands in the biological mechanisms underlying angiogenesis inhibition (important in anticancer therapy) and the controversy concerning angiogenesis induction (important in non-neoplastic diseases). As inhibition of angiogenesis represents one of the more promising, new approaches to anticancer therapy, PPAR- gamma ligands in addition to their established role as tumor cell cycle modulators could be implicated in future strategies for cancer treatment.

Alpha 2b-interferon inhibits rat liver regeneration after partial hepatectomy without affecting thymidine kinase activity.

The effect of alpha 2b-interferon administration on liver regeneration after partial hepatectomy in male Wistar rats was examined 24 hours after the operation. Tritium thymidine incorporation into liver DNA, liver mass restitution, mitotic index, and nuclear expression of proliferating cell nuclear antigen were determined as indexes of hepatic proliferation. Both early and late alpha 2b-interferon administration, 2 and 12 hours, respectively, after partial hepatectomy, at a dose of 3.3 x 10(4) IU per kg body weight, suppressed tritium thymidine incorporation and liver mass restitution (p < 0.001) when compared with that in untreated partially hepatectomized rats. The enzyme thymidine kinase (EC 2.7.1.21), a rate-determining enzyme of DNA biosynthesis, has been implicated in the suppression of proliferation in interferon-treated cell cultures. However, in the above-mentioned in vivo model of controlled cellular proliferation, thymidine kinase activity was not affected by alpha 2b-interferon administration, whereas DNA biosynthesis was inhibited. These findings, in contrast to previous observations in in vitro models, show that the inhibition of the in vivo liver regeneration by alpha 2b-interferon is not due to the inhibition of thymidine kinase activity. The expression of the cell cycle-related genes' products c-myc, p53, and c-erbB-2 proteins--which increase during the prereplicative phase that precedes DNA synthesis--was affected by interferon administration, being in accordance with liver proliferative status.