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The clearance of S. typhi Ty 2 and of a S. aureus strain by the isolated rat liver perfused in vitro with a synthetic serum free perfusate was studied. Bacteria were added to the perfusate at the initial concentration of 1x10(8) cells/ml. During perfusions the perfusate was sampled; after 30 min bile and liver samples were obtained and used for viable bacterial counts. After 30 min the amount of bacteria phagocytized greatly differed from one strain to the other: 30% for S. typhi Ty 2 and 100% for S. aureus. The end amount of viable bacteria recovered in the isolated liver was 7% for S. typhi Ty 2 and 80% for S. Aureus, thus indicating that for the latter strain greater clearance was not associated with an equally fast intracellular death.

A total of 159 hemophiliacs (149 treated) from our geographical area were screened in 1983 for serological evidence of HBV infection and biochemical evidence of liver disease. All were asymptomatic. HBsAg was detected in 16 cases (10%); anti-HBs and anti-HBc in 106 (67%); 19 (12%) subjects were susceptible to HBV. The HBV infection rate evaluated in 70 patients followed-up from 1980 to 1983 was 28% per year. The cumulative risk of HBV infection as well as the rate of seroconversion to HBV increased with increasing age and with increasing frequency of treatment given during the last 12 months. Anti-delta was detected in the serum of 5 (28%) out of 13 HBsAg-positive cases. Follow-up data showed that in 61% of subjects with liver dysfunction, hepatic damage could not be accounted for by HBV infection. AST and/or gamma-globulin increase was detected in 80% of patients. Abnormalities were more pronounced in HBsAg-positive cases and among them in subjects carrying anti-delta. Further follow-up studies are needed to clarify the long-term prognosis of liver disease in hemophiliacs.

Induction of endotoxin tolerance may cause resistance not only to endotoxin itself but also to the hepatotoxic effects of other membrane-active agents. To further study this effect, we tested whether endotoxin tolerance could ameliorate the adverse effects of taurolithocholate (TLCA) which causes cholestasis by altering liver plasma membrane organization. Isolated perfused rat livers from endotoxin-tolerant rats had a lower basal bile flow than control livers. However, a bolus addition of TLCA at 3 X 10(-5) or 5 X 10(-5) M in the perfusate caused a marked and prolonged decrease of bile flow in controls, but only a transient and significantly less pronounced diminution of bile flow in endotoxin-tolerant livers. Likewise, TLCA caused a significantly lower alteration of hepatocyte membrane permeability, as measured by sucrose permeability studies, in endotoxin-tolerant livers than in controls. Analysis of bile acid composition of bile from endotoxin-tolerant livers demonstrated that they excreted greater amounts of total bile acids, in particular TLCA and taurocholate, than controls. These results demonstrated a protective effect of endotoxin-tolerance against TLCA toxicity which may result from an altered interaction of TLCA with liver membranes and an increased clearance of TLCA.

The effects of ketoconazole (KT) on the hepatic excretory function was investigated in the isolated perfused rat liver. KT, at the concentrations of 5 X 10(-5) M or 10(-4) M caused dose-dependent decreases of the biliary bile acid concentration and excretion rate, with no significant effect on bile flow rates. Neither dose altered perfusate flow through the liver. Furthermore, at the same two concentrations, KT impaired the sulfobromophthalein transport in a dose-dependent manner. In contrast, the drug did not alter 14C-sucrose bile to perfusate ratio and did not cause enzyme release from the liver into the perfusate. The study demonstrates that KT possesses an intrinsic toxicity in the isolated perfused rat liver and suggests caution in the use of this drug in hepatopathic patients.

Studies were carried out using an isolated rat liver system to define: the contribution of exogenous phosphatidylcholine (PC) to biliary phospholipid secretion; and its hepatic metabolism during perfusion of the livers with conjugated bile salts with different hydrophilic/hydrophobic properties. A tracer dose of sn-1-palmitoyl-sn-2-[14C]linoleoylPC was injected as a bolus into the recirculating liver perfusate, under constant infusion of 0.75 mumol/min of tauroursodeoxycholate or taurodeoxycholate. The effects on bile flow, biliary lipid secretion, 14C disappearance from the perfusate and its appearance in bile, as well as hepatic and biliary biotransformation were determined. With both the bile salts, about 40% of the [14C]PC was taken up by the liver from the perfusate over 100 min. During the same period less than 2% of the given radioactivity was secreted into bile. More than 95% of the 14C recovered in bile was located within the identical injected PC molecular species. The biliary secretion of labeled as well as unlabeled PC, however, was significantly higher in livers perfused with taurodeoxycholate than tauroursodeoxycholate, while the reverse was observed with respect to bile flow and total bile salt secretion. The exogenous PC underwent extensive hepatic metabolization which appeared to be influenced by the type of bile salt perfusing the liver. After 2 h perfusion, the liver radioactivity was found, in decreasing order, in PC, triacylglycerol, phosphatidylethanolamine and diacylglycerol. In addition, the specific activity of triacylglycerol was significantly higher in tauroursodeoxycholate than in taurodeoxycholate-perfused livers (P less than 0.025), while the reverse was true for the specific activity of hepatic PC (P less than 0.01). Because taurodeoxycholate and tauroursodeoxycholate showed opposite effects on both biliary lipid secretion and hepatic PC biotransformations, we conclude that the hepatic metabolism of glycerolipids is influenced by the physiochemical properties of bile salts.

Estradiol-17 beta-D-glucuronide (E-17G), a metabolite of natural estrogen, is a potent cholestatic agent in vivo. We, therefore, studied the mechanisms of E-17G cholestasis using in vitro perfused rat liver system. Furthermore, since it has been postulated that sodium taurocholate (TC) may interfere with either uptake or biliary excretion of other steroid agents, we tested whether E-17G cholestasis could be modified by TC administration. During a constant infusion of TC at a physiological rate (0.50 mumole per min), a dose-dependent decrease of bile flow was observed after E-17G addition from 1.5 to 5 X 10(-5) M. E-17G decreased bile acid excretory rate but not bile acid concentration in bile. In separate experiments, TC was infused at different rates (0, 0.25, 0.50, and 0.75 mumole per min) into the perfusate over the entire experimental period, and E-17G was added at 1.75 X 10(-5) M. In this setting, E-17G cholestasis was diminished by increasing TC infusion rate and was prevented by TC at 0.75 mumole per min. Infusion of sodium dehydrocholate (0.75 mumole per min), a nonmicelle-forming bile acid, did not prevent E-17G cholestasis. During E-17G cholestasis, an increased biliary permeability to 14C-sucrose was observed. This effect was also prevented by TC, but not by sodium dehydrocholate which was infused at 0.75 mumole per min. The perfusate disappearance curves of 3H-E-17G at the different TC infusion rates showed no changes in the initial uptake phase, but a profound dose-dependent difference in the excretory phase.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors after giving some historical hints of vaccino-prophylaxis outline the various attempts made during the last twenty years, the present situation and the actual risks connected with the ways of administering of the antigen, in case of vaccination from a "public-health" point of view.

The role of surgery as an additional risk in transmitting "post-transfusion" hepatitis was investigated in a retrospective study on acute hepatitis occurring in 77 transfused patients, 293 transfused and operated patients and 243 hepatitis cases with history of surgery without transfusion. Hepatitis A patients admitted to the same centres in the same period were utilized as controls. In transfused patients the percentage of NANB hepatitis was higher than that of type B (61.0% vs. 36.4%), while in the operated not transfused group the percentage of type B was twice that of type NANB (63.4% vs. 32.5%). In transfused and operated cases intermediate values were observed. The age-adjusted measures of association between exposures and the different hepatitis types showed a lack of effect of transfusion and a dominant role of surgery in transmitting type B hepatitis. In contrast, NANB "post-transfusional" cases were actually a mixture of post-transfusional and post-surgical cases, since both these exposures were found to be significantly associated with the disease. Our results suggest that studies on the incidence and the etiology of post-transfusion hepatitis should take into account the risk of surgical exposure which might have occurred.

To investigate the mechanisms of erythromycin cholestasis, the effects of erythromycin estolate (EE) on the excretory function of the isolated perfused rat liver and on liver plasma membrane (LM) preparations were studied and compared to those of erythromycin base (EB) and lauryl sulfate (LS), added alone or in combination. EE (at 125 to 200 microM) caused dose-dependent reductions of bile and perfusate flows, bile acid (BA) excretion, and biliary BA concentration. The alterations of the excretory function were only in part due to the decreased perfusate flow. In contrast, both 200 and 300 microM concentrations of EB elicited similar choleretic responses, which were presumably related to the osmotic activity of the drug excreted in the bile. LS did not affect hepatic excretory functions. However, the simultaneous addition of EB and LS resulted in a rate of bile flow lower than that observed with EB alone. EE, but not EB, increased canalicular permeability to [14C]sucrose as measured by bile to plasma (B:P) ratio. Neither drugs altered [14C]erythritol B:P ratio. In LM preparations both Na+,K+- and Mg2+-ATPase activities were inhibited in a dose-dependent manner by EE, but not by EB. The data suggest that EE could affect bile flow by inhibiting cotransport of Na+ and BA and by altering LM permeability and support the view that the effect of erythromycins on the liver may be related to their surface activity.

We evaluated the effect of Amphotericin B, a polyen antimycotic agent, on the excretory functions of the isolated perfused rat liver. At 5 X 10(-6) and 10(-5) M, Amphotericin caused a rapid dose-dependent cholestasis. This effect was paralleled by an increase in canalicular permeability, as evaluated by sucrose C14 B/P ratio. The data indicate that Amphotericin B is a potent cholestatic agent in vitro and suggest that caution should be exercised in the use of this drug in hepatopatic patients.

The authors describe a case of partial monosomy 9p in a newborn infant, with breakpoint in the region p221, due to a father's balanced translocation with karyotype 46 XY t(9;16)(p221;q224). The phenotypical features of our patient reproduce those reported in other 35 cases described up to now in the literature: trigonocephaly, upward slanting palpebral fistures, little and horizontal mouth, disproportionally long fingers and toes. Some peculiar clinical and cytogenetical features of the case are discussed, particularly the early closure of the sternal body ossification centers (already detected during the prenatal life), the partial agenesia of the splenium corporis callosi and the partial anomalous pulmonary venous return. The Authors point out the importance of an early diagnosis, based on the awareness to the clinical abnormalities and dysmorphisms, in order to provide for an adequate and opportune genetic counseling.

The possibility that endotoxin pretreatment could prevent the hepatotoxic effects of erythromycin estolate (EE) was investigated using the isolated perfused rat liver. The addition of E. coli endotoxin (25 micrograms/ml) to the perfusate, 30 min prior to EE administration at 150 or 200 microM, significantly ameliorated the decreases in bile and perfusate flow caused by either concentrations of the drug in control liver preparations. This phenomenon was also studied using liver isolated from rats pretreated in vivo with endotoxin for three days. In these preparations, EE at both concentrations did not alter bile flow and caused reductions of perfusate flow which were far less than those observed in untreated control livers. Furthermore, in livers from endotoxin-treated rats EE induced less reduction of bile acid excretion and, at 150 microM, it did not increase the bile to perfusate ratio of sucrose seen in control preparations after the drug, which may be an expression of altered hepatocytic membrane permeability. Since it is known that both endotoxin and EE interact with membranes, it is suggested that the "protective" effects of endotoxin may occur at the membrane level.

We investigated the incidence of HBsAg carriers among blood donors from 107 Italian blood banks during 1986. The overall prevalence of HBsAg carriers was 1.98%. This percentage was higher in Southern (2.69%) than in Northern (1.78%) or Central Italy (0.83%). Notable differences were found in the various regions and in single centres belonging to the same region. In some small areas a prevalence of carriers as high as 10% was recorded. Most carriers had normal aminotransferase values, HBeAg was detected in 8.8% of the carriers and anti-delta in 2.9% of them. The figures from this study still suggest a persistence of an intermediate endemicity level of HBV infection in Italy, with some hyperendemic niches.

Endotoxemia, measured by Limulus amebocyte lysate (LAL) assay, was found to be present in 34 (46%) out of 72 patients with liver cirrhosis and in 7 (22%) out of 32 patients with chronic active hepatitis (CAH). In cirrhotics, no difference in the alteration of liver function tests and renal function was found between the two groups. However, 18 months mortality was higher in the group with endotoxemia in respect to the group without endotoxemia (p less than 0.05). In CAH patients, the Limulus-positive group showed a higher level of serum gamma-globulins, compared to the Limulus-negative group (p less than 0.005). Moreover, CAH patients with a positive LAL test showed marked histological activity and bridging necrosis more frequently than those with a negative test. This suggests that in these patients the appearance of endotoxemia may indicate a more advanced stage of the disease.