BACKGROUND:Several small studies have reported a lower response rate to interferon alfa among black patients with chronic hepatitis C infection than among white patients. The increased prevalence of infection with hepatitis C virus (HCV) genotype 1, which has a lower response rate than other genotypes, has been suggested as the cause.METHODS:We treated 100 black patients and 100 non-Hispanic white patients with chronic hepatitis C with peginterferon alfa-2b and ribavirin for 48 weeks. Enrollment was controlled so that the two groups had similar proportions of patients with genotype 1 infection. The primary end point was a sustained virologic response, which was defined as a negative test for serum HCV RNA six months after the completion of therapy.RESULTS:In both cohorts, 98 percent of patients had genotype 1 infection. The rate of sustained virologic response was higher among non-Hispanic white patients than among black patients (52 percent vs.19 percent, P<0.001). The black patients also had significantly lower rates of virologic response at 12 weeks and at the end of treatment. Multivariable analyses examining sociodemographic and clinical characteristics found that black race was the only variable significantly associated with the difference in response rate.CONCLUSIONS:Black patients with chronic hepatitis C have a lower rate of response to treatment with peginterferon alfa-2b and ribavirin than non-Hispanic white patients, a difference that is not explained by differences in the viral genotype.

Among patients whose stones were successfully fragmented (<3mm), the percentage of GB hypomotility was significantly lower in patients with complete stone clearance (25.2%) than in patients without complete clearance (40.3%)(p-0.042). In vitrostudy; TLC (g/dl) CGR FCM Vmax NT(hr) Crystal habits 3 0 0.020 0.015 168 arch 6 0.0013 0.190 0.253 70 plate & arch 9 0.0044 0.220 0.540 60 plate & arch 12 0.0064 0.285 0.222 30 plate & arch (CGR, Crystal growth rate; FCM, Final crystal mass; Vmax, Maximal vesicle turbidity; NT, Nucleation time)Summary and conclusions: The success rate was not affected by aging, although GB function was significantly damaged in association with ages.The fact that a lower TLC and retarded NT were evident in old ages suggests that the lithogenic state significantly differs with aging.In fact, a physicalchemical state of bile lipids was stabilized with diluting of bile as reflected by CGR in in vitro study.Thus, aging modulate bile metastability through altering GB motility, presumably determining the efficacy of gallstone treatment.This study was supported, in part, by the Ministry of Education of the Japanese Govemment,

The concentration dependence of the 500 MHz 1H-NMR spectra of taurocholate, taurochenodeoxycholate, taurodeoxycholate, and the monosulfate esters of taurochenodeoxycholate has been examined at 0.154 M NaCl in D2O. The resonances of the C18, C19, and C21 methyl groups and the C23 methylene group are differentially broadened with respect to the C25 and C26 methylene and C7 (or C12) methine groups with increasing bile salt concentration for each of the bile salts studied. These data confirm hydrophobic association and indicate that the side chain contributes to the hydrophobic surface of the bile salt. The chemical shift difference of the anisochronous C23 methylene protons is different in monomer and aggregate form. The C25 methylene protons are isochronous in monomeric form but anisochronous in aggregate form. The concentration dependence of the observed chemical shifts has been analyzed to estimate the critical concentration associated with the onset of these changes. The conformer population about the C22-C23 bond changes before the anisochronicity of the C25 methylene protons develops. This indicates that the C23 methylene group is affected by the initial stages of self-association, whereas specific motional constraints about the N-C25 bond in the taurine moiety are only induced in large primary micelles. The difference in the chemical shift of the C25 methylene protons depends on the structure of the bile salt. The relative magnitude of the shift differences is not altered by the presence of phosphatidylcholine. The data suggest that in primary micelles or mixed micelles the taurine moiety conforms to segregate the hydrophilic groups of the bile salt and effects greater van der Waals' contact between the hydrophobic surfaces.

The effect of sulfate esterification of the 3 alpha- or 7 alpha-hydroxyl groups of taurochenodeoxycholate on calcium binding was studied at 0.154 M NaCl in the presence and absence of phosphatidylcholine using a calcium electrode. For comparison, similar studies were made with taurochenodeoxycholate, taurodeoxycholate, and taurocholate. No high affinity calcium binding was demonstrable for any of these bile salts in pre-micellar solutions. Taurine-conjugated bile salts have greater affinity for calcium when in a micellar form. At elevated bile salt concentrations, the calcium binding of unsulfated dihydroxy taurine conjugates was similar to that of the monosulfate esters of taurochenodeoxycholate. The presence of phosphatidylcholine decreased calcium binding of the unsulfated dihydroxy bile salts and slightly increased calcium binding by taurocholate. However, the addition of phosphatidylcholine to monosulfate esters of taurochenodeoxycholate results in large increments in calcium binding. The results indicate that increased calcium binding due to the presence of phosphatidylcholine in bile salt solutions depends, in part, on the hydrophilicity of the bile salt and that the interaction of monosulfate esters of taurochenodeoxycholate with phosphatidylcholine leads to the formation of a high affinity calcium binding site.

The effect of the 3a- and 7a-monosulfate esters of taurochenodeoxycholate on bile flow and biliary lipids was com- pared to the effect of unsulfated taurochenodeoxycholate. Test bile salts were infused directly into the portal circulation through a catheter introduced into the splenic pulp. Recovery of unsul- fated and sulfated bile salts was complete; no biotransformation of any of the administered compounds was noted. Equivalent choleresis was noted in response to administration of each of the test bile salts. Of particular interest, the biliary cholesterol and phospholipid content was tightly linked to biliary bile salt mono- sulfates; the slope of the line describing the relationship between bile salts and lipids was similar to that for the unsulfated bile salt. The critical micellar concentration of the 3a- and 7a- monosulfate esters was 19 mM and 18 mM, respectively. M Sulfation of taurochenodeoxycholate, therefore, does not impair its bile secretory function. Despite a higher critical micel- lar concentration, biliary lipid excretion with monosulfate esters is equivalent to that seen with unsulfated bile salt. The role of hydrophobiclhydrophilic balance in the promotion of biliary lipid excretion may need to be redefined.-Stevens, R. D., L. Lack, R. H. Collins, W. C. Meyers, Jr., and P. G. Killenberg. Effects of monosulfate esters of taurochendeoxycholate on bile flow and biliary lipids in hamsters. J. Lipid Res. 1989. 30: 673- 679.

DU-PAN-2 is a high-molecular-weight glycoprotein defined by a murine monoclonal antibody (MAb) elicited against a human pancreatic adenocarcinoma cell line. This MAb recognizes an oncofetal antigen present on the surface of normal pancreatic and bile-duct epithelium, normal bronchus epithelium, and some adenocarcinomas. Elevated levels of the antigen (greater than 400 U/ml) have been detected in the serum of 79% of patients with adenocarcinoma of the pancreas and in a small percentage of patients with other adenocarcinomas, by means of a competition radioimmunoassay. Here, we have studied DU-PAN-2 antigen levels in sera of patients with a spectrum of hepatobiliary diseases and controls. Serum DU-PAN-2 antigen was elevated in 59% of 112 patients with non-malignant hepatobiliary diseases and in 50% of hepatoma patients. None of 50 healthy controls had elevated serum DU-PAN-2 levels. Patients in every category of hepatobiliary disease studied had elevated median serum DU-PAN-2 levels; the highest median levels were seen in patients with primary biliary cirrhosis (1,296 U/ml) and the lowest in stable cirrhosis (300 U/ml). Elevated serum DU-PAN-2 levels in one patient with primary biliary cirrhosis and in one patient with hepatoma returned to normal following liver transplantation. Serum DU-PAN-2 levels did not correlate well with alkaline phosphatase, 5'-nucleotidase, bilirubin, or alpha-fetoprotein. Using an immunoperoxidase technique on formalin-fixed, deparaffinized liver sections, we showed that DU-PAN-2 MAb reacted heterogeneously with bile-duct epithelium but never stained hepatocytes or hepatoma cells. While serum DU-PAN-2 levels may be useful in detecting and monitoring pancreatic adenocarcinoma, they are not specific for this disease.

Rat liver bile sulfotransferase activity can be divided into a fraction that reacts with a monoclonal antibody (PK1B) and another fraction that does not. This work was performed to analyze the known response of hepatic bile acid sulfotransferase activity to androgens and estrogens by determining the effect of treatment on the proportion of bile acid sulfotransferase activity that possessed the epitope for PK1B monoclonal antibody. Activity in treated animals was further characterized by high-performance liquid chromatography (HPLC) analysis following purification by PK1B-immunoadsorption chromatography. The results indicate that estrogens and androgens affect the subset of enzyme activity that has the PK1B epitope more than the population that does not. HPLC demonstrates that increases and decreases in activity that follow treatment with androgens and estrogens are mirrored by the proportion of the PK1B-reactive protein that exhibits a relative molecular weight (Mr) greater than 170,000. Radial immunodiffusion assays of hepatic supernatant using a polyclonal antibody raised against PK1B-reactive bile acid sulfotransferase show that changes in specific activity that follow treatment are the result of changes in enzyme protein concentration.

A monoclonal antibody, PK1B, directed against rat liver bile acid sulfotransferase was used for the purification and characterization of the enzyme. Incubation of rat liver supernatant with the antibody followed by immunoprecipitation with Staphylococcus aureus cells demonstrated that PK1B reacted with 90% of the enzymatic activity present in the liver supernatant from female rats and 40 to 50% of the activity in male liver preparations. Immunoadsorption chromatography with PK1B bound to Sepharose isolated active enzyme which was purified greater than 75-fold. Sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis of this preparation in the presence of 2-mercaptoethanol demonstrated three polypeptides: Mr 29,500; 32,500, and 34,000. Western blot analysis indicated that PK1B recognized an epitope which was found only on the Mr 29,500 polypeptide. Two-dimensional gel electrophoresis associated the enzymatic activity with this Mr 29,500 band. High-pressure liquid chromatographic analysis of immunopurified enzyme defined three distinct, enzymatically active protein populations: I (Mr 400,000 to 170,000); II (Mr 130,000), and III (Mr 43,000). An Mr 29,500 polypeptide was the sole constituent of Peaks I and III and a major constituent of Peak II. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis in the presence and absence of 2-mercaptoethanol indicated that in Peak II, catalytically active Mr 29,500 protein is associated with the other two polypeptides by disulfide bonds. In contrast, Peak I consists of a polymer of Mr 29,500 polypeptide which is independent of disulfide interaction.

The effect of estrogens and androgens on hepatic glycolithocholate sulfotransferase activity was studied in male rats. Significant increases in specific activity were noted following treatment of rats for 21 days with 17 beta-estradiol, 17 alpha-ethynylestradiol, and the nonsteroidal estrogen agonists nafoxidine, tamoxifen, and diethylstilbestrol. Similar treatment of male rats with 5 alpha-dihydrotestosterone, hydrocortisone, norethindrone, and prolactin did not affect activity. To further assess the effect of androgens, male rats were castrated. Glycolithocholate sulfotransferase activity increased fivefold by 14 days after castration. Treatment of castrated rats with 5 alpha-dihydrotestosterone prevented the increase and maintained activity at the level of sham-operated animals. Castrated animals exhibited an additional increment in activity following treatment with 17 alpha-ethynylestradiol: specific activity in these animals rose to levels comparable with those measured in untreated female rats. These data suggest endogenous androgens maximally suppress hepatic glycolithocholate sulfotransferase activity in male rats. The data also indicate that activity is stimulated by estrogenic compounds of varied chemical structure and that stimulation is not solely due to suppression of androgen release by the testes as a consequence of estrogen treatment.