Hepatocellular proliferation and development of hepatocellular carcinoma: a case-control study in chronic hepatitis C

Patients with hepatitis C have an increased risk of developing hepatocellular carcinoma (HCC). This is related to the stage of chronic liver disease, as characterized histologically by hepatic fibrosis and architectural distortion, but it is unclear whether histological markers can define the risk of developing HCC. We conducted a case-control immunohistochemical study of Ki-67, a marker for hepatocellular proliferation, in livers of 18 patients who had developed HCC more than 2 years after the biopsy specimen had been taken. Using conditional logistic regression analysis, the results were compared with 18 selected controls, who were age-matched patients with hepatitis C of similar histological stage who had not developed HCC. We also examined livers for cellular dysplasia, p53 mutations, and bcl-2 overexpression, and assessed whether the results could be correlated with demographic and disease-related variables, such as gender, region of birth, alcohol consumption, severity of liver disease, HCV genotype, and markers of hepatitis B virus (HBV) infection. Livers from patients who developed HCC were more often positive for Ki-67 (13 of 18 [72%] v 9 of 18 [50%]; P = .06) and tended to have higher mean Ki-67 scores (6 +/- 7.5 v 3 +/- 4.4; P = .10) compared with control cases. In the HCC-predisposed group, three livers showed large cell dysplasia, two were positive for p53 mutations, and two for bcl-2 overexpression. In contrast, in the non-HCC group, only one case had dysplasia, and none were positive for immunostaining for p53 or bcl-2 mutations. With the exception of one case, all livers with large cell dysplasia or p53 mutations and bcl-2 overexpression were also positive for Ki-67. Twelve (55%) of the 22 Ki-67-positive cases were anti-HBc-positive in the serum, in contrast to 2 of 14 (14%) patients in the Ki-67-negative group (P = .01). Patients with evidence of past infection with HBV were more often Ki-67 positive than those who had no evidence of past infection (85% [11 of 13] v 45% [10 of 22]; P = .02). There were no other associations between demographic or disease-related variables and Ki-67 expression. Increased hepatocellular proliferative activity, as assessed by Ki-67 expression, may be one factor indicative of an increased risk of developing HCC among patients with chronic hepatitis C. Furthermore, past infection with HBV appears to be an important correlate of increased hepatocellular proliferation in hepatitis C.     

Islet transplantation as a treatment for diabetes

BACKGROUND: The microvascular complications of diabetes are directly linked to hyperglycemia. Beta-cell failure is a critical factor in regulation of blood sugar levels. However, only a small proportion of persons with type 1 and type 2 diabetes obtain sufficient glycemic control to avoid complications. METHODS: There are two routes for beta-cell replacement, transplantation, and a mechanical beta cell equivalent. Beta-cell replacement therapy is a potential treatment modality, since diabetes is caused by beta-cell failure. RESULTS: An obvious path for glycemic control is some form of beta-cell replacement therapy. Successful islet transplantation is a difficult challenge, but current achievements with human pancreas transplants and islet allografts may greatly improve glycemic control. CONCLUSION: Beta-cell replacement therapy is an accepted treatment modality for diabetes.     

First-trimester growth and the risk of low birth weight

BACKGROUND: Previous studies have demonstrated a correlation between first-trimester size and birth weight. It is not known, however, whether low birth weight is related to first-trimester growth. We sought to determine whether the risk of low birth weight and birth weight that was low for gestational age is related to the size of the embryo or the fetus in the first trimester. METHODS: From a data base of ultrasound records of more than 30,000 pregnancies, we identified women who had no important medical problems, a normal menstrual history, and a first-trimester ultrasound scan in which the crown-rump length of the embryo or fetus had been measured. We examined the relation between the outcome of 4229 pregnancies and the difference between the measured and the expected crown-rump length in the first trimester, expressed as equivalent days of growth. RESULTS: A first-trimester crown-rump length that was two to six days smaller than expected was associated with an increased risk (as compared with a normal or slightly larger than expected crown-rump length) of a birth weight below 2500 g (relative risk, 1.8; 95 percent confidence interval, 1.3 to 2.4), a birth weight below 2500 g at term (relative risk, 2.3; 95 percent confidence interval, 1.4 to 3.8), a birth weight below the fifth percentile for gestational age (relative risk, 3.0; 95 percent confidence interval, 2.0 to 4.4), and delivery between 24 and 32 weeks of gestation (relative risk, 2.1; 95 percent confidence interval, 1.1 to 4.0), but not with delivery between 33 and 36 weeks (relative risk, 1.0; 95 percent confidence interval, 0.7 to 1.5). CONCLUSIONS: Suboptimal first-trimester growth may be associated with low birth weight, low birth-weight percentile, and premature delivery.     

Lupus anticoagulant, anticardiolipin antibodies and hepatitis C virus infection in thalassaemia

Anticardiolipin antibodies (ACA) and lupus anticoagulant (LA) have been detected in patients with hepatitis C virus (HCV) infection and have been associated in autoimmune diseases (i.e. systemic lupus erythematosus) with an increased risk of thromboembolic events. Because of the high prevalence of HCV infection and the thrombotic risk described in thalassaemia we decided to investigate the prevalence of ACA and LA in a cohort of 68 thalassaemia patients. We found a high prevalence (34%) of beta2-glycoprotein I independent ACA in our thalassaemia patients which was related to HCV infection. None of patients developed any complications related to antiphospholipid antibodies (APL); therefore the clinical significance of positivity for APL in patients with HCV infection is at present unclear. In conclusion, the results of our study indicate that ACA in the serum of HCV-infected thalassaemic patients exhibit the characteristics of natural autoantibodies rather than those of the pathogenic autoantibodies that are found in patients with systemic lupus erythematosus.     

Determinants of dietary intake in a sample of white and Mexican-American children

Using a modified method consisting of chromatography on phenyl-Sepharose, Q-Sepharose, and hydroxyapatite, we isolated a highly purified heat shock protein with molecular weight 90 kD (Hsp90) from rabbit liver. The isolated protein was recognized on immunoblot by commercially available monoclonal anti-Hsp90 antibodies. The chromatographic properties, interaction with actin and calmodulin, phosphorylation in the presence of Mg-ATP, and one-dimensional peptide maps of rabbit liver Hsp90 are similar to the corresponding properties of Hsp90 isolated from other sources. In the presence of soluble carbodiimide and N-hydroxysuccinimide, rabbit liver Hsp90 can be cross-linked with calmodulin, troponin C, troponin I, and calponin. The data obtained indicate that Hsp90 may participate in the assembly of regulatory proteins of the actin filament.     

DNA synthesis of human, mouse, and rat mammary carcinomas in vitro: influence of insulin and prolactin

Carcinomatous mammary tissues, derived from six spontaneously arising mouse mammary tumors, six DMBA-induced rat mammary tumors, and 26 biopsy specimens of human breast tumors, were processed into slices and each tumor was inidvidually cultured for two days in Medium 199. The influence of bovine insulin (5.0 mug/ml) and ovine prolactin (10.0 mug/ml) on H3-thymidine incorporation into DNA was determined on the cultured tumor slices. Insulin consistenly (p less than 0.05-0.01) increased the incorporation of H3-thymidine into DNA of the organ cultures of mouse, rat, and human mammary carcinoma slices. The stimulatory effect of insulin was quantitatively more prominent in the mouse tumor slices than in the rat or human slices. The addition of prolaction to the insulin-containing culture medium further increased significantly (p less than 0.001) the incorporation of H3-thymidine into DNA of rat mammary carcinoma slices but had no significant effect on cultures of either mouse or human mammary carcinomas. The addition of prolactin to insulin and hydrocortisone-enriched medium containing slices of 20 individually cultured human breast carcinomas did not significantly influence the mean incorporation of H3-thymidine into DNA. However, a very small fraction (approximately equal to 15%) of these human breast carcinomas responded to prolactin by increasing the incorporation of H3-thymidine into DNA to a degree quantitatively comparable to the prolactin-sensitive, DMBA-induced rat mammary carcinoma. These results suggest that a very small fraction of human breast malignancies may respond to the growth-stimulatory effects of prolactin, but that the vast majority mimic more closely the prolactin-independent mouse mammary carcinoma.