Seroprevalence of hepatitis B and C viral markers in patients with primary hepatocellular carcinoma in Singapore

This paper reviews studies on the basic principles of biostimulation of wound healing by various low-energy lasers. It looks at the mechanism of action of biostimulation as well as the laser's effect on cell proliferation, collagen synthesis, and would healing.     

Differences of resected hepatocellular carcinoma with hepatitis B or C virus

BACKGROUND/AIMS: The purpose of this study was to clarify the clinicopathologic differences of hepatocellular carcinoma associated with the hepatitis B versus the hepatitis C virus. METHODOLOGY: One hundred and sixty-eight patients with resected hepatocellular carcinoma were tested for viral hepatitis. Ten (6%) had both the hepatitis B surface antigen and antibodies to the hepatitis C virus. Thirty-three (20%) had neither marker. Sixteen (9%) had only the hepatitis B surface antigen (group B), and 109 (65%) had only antibodies to the hepatitis C virus (group C). We compared groups B and C clinicopathologically. RESULTS: The mean tumor diameter was larger in group B than in group C (6.3 cm vs 3.4 cm), while group B patients were younger than group C (48 yrs vs 62 yrs, p<0.0001). Poor liver function, histologic cirrhosis and chronic active hepatitis were frequently found in group C. The 1- and 2-year tumor-free survival rates following surgery in group B were 67% and 33%, and those in group C were 73% and 49%. The 1-, 2-, and 3-year survival rates following surgery in group B were 78%, 68%, and 0%, while those in group C were 92%, 83%, and 76% (p=0.0189). CONCLUSIONS: Hepatocellular carcinoma with concomitant hepatitis B viral infection was found to present as larger tumors in younger patients with less severe liver dysfunction. Hepatocellular carcinoma with concomitant hepatitis C viral infection was often detected in follow-up studies when it was small.     

Frequent detection of hepatitis B virus X-gene DNA in hepatocellular carcinoma and adjacent liver tissue in hepatitis B surface antigen-negative patients

Hepatitis B virus is associated with human hepatocellular carcinoma. We performed polymerase chain reaction for the X, C, S, and preS2/S regions of the viral genome in 23 hepatitis B surface antigen-negative hepatocellular carcinomas and adjacent liver. Hepatitis B viral genomes were detected in 17 of 23 tumors and adjacent tissues (73.9%). Among recognized transactivators, the X gene was present in 16 (69.6%) cases of hepatocellular carcinoma, but preS2/S was detected in only 7 (30.4%). Hepatitis B virus C and S regions were detected in 3 (13.0%) and 9 (39.1%) hepatocellular carcinomas, respectively. Serologic study revealed antibodies to hepatitis B surface antigen, hepatitis B core antigen, and hepatitis B e antigen in 14 patients; among these, X-gene DNA was detected in 12 of 14 tumors (85.7%). The X gene was also detected in 4 of 9 tumors of seronegative patients. The X gene, present in many hepatocellular carcinomas, may promote hepatocellular carcinoma in hepatitis B surface antigen-negative patients.     

Surgical significance of telomerase activity in noncancerous liver tissue from patients with hepatocellular carcinoma

Telomerase activity has been detected in tissue from noncancerous liver of patients with chronic liver disease, but its functional significance remains to be elucidated. We therefore evaluated the telomerase activity in surgically obtained noncancerous liver tissue from 20 hepatocellular carcinoma (HCC) patients. Two samples of noncancerous liver tissue were obtained from each patient: one from the parenchyma adjacent to the HCC nodules of the resected specimen; the other from the parenchyma distant from the HCC nodules of the remnant liver. Telomerase activity was assayed by a non-radioisotope quantitative system based on "TRAP-eze." Five samples from the noncancerous liver tissue adjacent to the HCC nodules (25.0%) were telomerase-positive; all such cases showed high-grade malignant potential, such as intrahepatic metastasis and/or portal vascular invasion and infiltration of the fibrous capsule in the corresponding HCC nodules, and telomerase positivity showed neither a relationship with the histological activity index scores nor a correlation with liver function. Interestingly, no telomerase activity was detected in any of the 20 samples obtained from the parenchyma of the remnant liver. These results indicate that telomerase in noncancerous liver tissue is associated not with the hepatic condition accompanying HCC, but with the biological characteristics of the tumor itself, and may derive from infiltrating cancer cells. Determination of telomerase status may aid in designing more effective surgical procedures.     

Human hepatitis B virus and hepatocellular carcinoma. I. Experimental infection of tree shrews with hepatitis B virus

A cross-sectional study involving 771 children under the age of one year, was carried out in a traditional area of urban Ilorin, Nigeria, to determine how socio-economic conditions and feeding practices relate to diarrhoeal disease among infants. After adjustment has been made (through logistic regression) for covariates, five factors had significant association with diarrhoeal disease. These are the age of the child, parity, mother's education, availability of household kitchen and the feeding of semi-solid food to the infants. The lowest diarrhoeal rate occurred in infants aged 0-3 months while the highest rate occurred among infants seven to nine months old (Odds Ratio = 4.2). Children who were of the fifth or higher birth order had significantly higher risk of diarrhoea when compared with those who were of the first or second birth order (OR = 1.62; P < 0.05). Children of mothers with secondary education had significantly higher risk of diarrhoea compared with children of illiterates (OR = 1.9; P < 0.05). Households that had no kitchen had significantly higher risk of infantile diarrhoea than households with kitchen facilities (P < 0.01). Finally, infants receiving semi-solid food had higher risk of diarrhoea compared to those children not receiving semi-solid food (P < 0.05). Diarrhoeal disease awareness campaign to educate mothers on the dangers of childhood diarrhoea and how to prevent it, through proper hygiene, especially, food hygiene, is advocated.     

Influence of viral hepatitis status on operative morbidity and mortality in patients with primary hepatocellular carcinoma

The influence of associated viral hepatitis status on 119 patients with primary hepatocellular carcinoma (HCC) undergoing hepatic resection was investigated. Operative morbidity and mortality were examined in three patient groups: 31 patients (group B) positive for hepatitis B surface antigen (HBsAg), 14 (group Be) positive for both HBsAg and hepatitis B e antigen, and 74 (group C) positive for hepatitis C virus antibody (HCVAb). Preoperative liver function in groups Be and C was similar and more impaired than that of patients in group B; combined active hepatitis was seen most frequently in group C (68 per cent). The tumour size in group B was significantly greater than that in groups Be and C. Postoperative complications occurred more frequently in group C (39 per cent) and early postoperative deaths, other than those from cancer, were seen in nine patients positive for HCVAb, of whom three developed postoperative liver failure. Patients with HCC and hepatitis B without seroconversion as well as hepatitis C frequently have active hepatitis, which may impair liver function and play an important role in operative morbidity and mortality.     

Evolution of hypervariable region 1 of hepatitis C virus in primary infection

The hypervariable region 1 (HVR-1) of the putative envelope encoding E2 region of hepatitis C virus (HCV) RNA was analyzed in sequential samples from three patients with acute type C hepatitis infected from different sources to address (i) the dynamics of intrahost HCV variability during the primary infection and (ii) the role of host selective pressure in driving viral genetic evolution. HVR-1 sequences from 20 clones per each point in time were analyzed after amplification, cloning, and purification of plasmid DNA from single colonies of transformed cells. The intrasample evolutionary analysis (nonsynonymous mutations per nonsynonymous site [Ka], synonymous mutations per synonymous site [Ks], Ka/Ks ratio, and genetic distances [gd]) documented low gd in early samples (ranging from 2. 11 to 7.79%) and a further decrease after seroconversion (from 0 to 4.80%), suggesting that primary HCV infection is an oligoclonal event, and found different levels and dynamics of host pressure in the three cases. The intersample analysis (pairwise comparisons of intrapatient sequences; rKa, rKs, rKa/rKs ratio, and gd) confirmed the individual features of HCV genetic evolution in the three subjects and pointed to the relative contribution of either neutral evolution or selective forces in driving viral variability, documenting that adaptation of HCV for persistence in vivo follows different routes, probably representing the molecular counterpart of the viral fitness for individual environments.     

Significance of the minor i and t determinants of hepatitis B virus in hepatocellular carcinoma

Stored sera from asymptomatic hepatitis B virus (HBV) carriers and hepatitis B virus surface antigen-positive hepatocellular carcinoma (HCC) patients were tested for HBV subtypes, such as subtype determinants d, y, w, r and also antigenic determinants isoleucine (i) and threonine (t) by direct S gene nucleotide sequencing. Significant changes in minor i and t determinants in hepatocellular carcinoma patients with adr hepatitis B carriers were seen. The adr subtype with t determinant was present in 14/25 (56%) of HCC patients compared with only two of 28 (7%) in asymptomatic hepatitis B carriers (P<0.001). However, the adr subtype with i determinant was present in nine of 25 (36%) of the HCC patients and also present in 24/28 (86%) of asymptomatic carriers (P<0.001). No significant changes were seen with the adw subtypes. These results show that i and t minor determinant changes are more common with adr subtypes associated with HCC than with the adw subtype. Whether these subtle changes are pathologically relevant or only a polymorphism of hepatitis B genotypes will depend on subsequent follow-up studies.     

Inhibition of hepatocellular carcinoma development in hepatitis B virus transfected mice by low dietary casein

In a comprehensive human ecological study, primary liver cancer has been shown to be highly significantly associated with 1) the prevalence of persistent infection with hepatitis B virus (HBV) and 2) plasma cholesterol concentrations that are, in turn, associated with the consumption of animal based foods. In rat studies, aflatoxin-induced hepatocellular carcinoma is substantially prevented by decreasing the intake of animal based protein (casein), a hypercholesterolemic nutrient. Thus the development of primary liver cancer associated with persistent HBV infection or with aflatoxin exposure may be controlled by reduced intake of animal-based proteins. Transgenic mice transfected with an HBV gene fragment containing the viral transactivator of hepatis B virus, HBx, which induces the formation of hepatocellular carcinoma, were used to examine the ability of dietary casein to modify tumor formation. Reducing the concentration of dietary casein to 6% from the traditional level of 22% markedly inhibited (by 75%) hepatic tumor formation in these transgenic mice. Tumor development also was substantially altered by interchanging dietary casein concentration well after tumor development had begun (at 8 months), increasing by 173% from the expected yield when casein intake was increased and decreasing by 99% when casein was reduced. These findings suggest that the development of liver tumor formation among individuals persistently infected with HBV may be controlled by minimizing or eliminating the intake of animal protein-based foods.     

Analysis of a viral integration event in a CG-rich region at the 1p36 human chromosomal site

The preinsertion site of an adenovirus-5/simian virus 40 recombinant construct (Ad5/SV40) has been cloned and sequenced. Our data suggest that viral integration has occurred in a genomic region which has been the target of multiple events of Alu element retropositions within a TAA minisatellite. Extensive homologies between the left viral end and the host cellular DNA were also observed. The compositional similarity between Adenoviridae and the region of viral integration is consistent with the observed insertion of exogenous DNA in isochores of similar composition [G. Bernardi, Annu. Rev. Genet. 23 (1989) 637-661].     

Past exposure to hepatitis B virus as a risk factor for hepatocellular carcinoma in patients with chronic liver disease

Maltitol is a disaccharide alcohol that is produced by hydrogenation of maltose and exhibits resistance to intestinal disaccharidases. We demonstrated previously that maltitol stimulated transepithelial diffusional calcium transfer in the ileum, accompanied by an elevation of intestinal calcium absorption as well as calcium retention in the body. In this study we examined whether the maltitol-induced increase in the diffusional transfer of intestinal calcium absorption leads to an alteration of the physical properties of bones in the weanling rats which exhibit the maximal level of intestinal active calcium absorption. Rat pups were removed from dams at 24 d of age and were fed the diets containing either maltose (control) or maltitol and a requisite amount of calcium (0.52%) for 21 d. Balance studies performed during the final 5-d period showed that maltitol-fed rats had greater calcium retention and calcium absorption. The breaking force of femoral bones was 13% greater in the rats fed the maltitol diet than in controls. The calcium content and dry weight of both femurs and tibias, as well as the bone mineral density of tibias, were elevated in the rats fed the maltitol diet. In a separate experiment, gastric intubation of maltitol-containing diet increased the serum calcium concentration in the portal vein at 2 and 4 h compared to controls. These results indicate that the maltitol-induced increase in the intestinal calcium absorption through paracellular pathway leads to enhancement of the calcium content and the breaking strength in the bone of weanling rats.     

Antibodies in human sera specific to hypervariable region 1 of hepatitis C virus can block viral attachment

It has been postulated that antibodies specific to the hypervariable region 1 (HVR1) within the putative envelop protein E2 of hepatitis C virus (HCV) can neutralize virus. We studied such antibodies in sera of patients who were infected in a single-source outbreak by a contaminated anti-D immunoglobulin preparation (HCV-AD78). The nucleotide sequences of cDNAs encoding HVR1 of HCV-AD78 were determined. The four major variants (HVR1.A, B, C, and D) were expressed as fusion proteins in Escherichia coli. Sixty-seven percent of sera contained antibodies to HVR1.A. Sera unrelated to infection of the outbreak also recognized HVR1.A but to a lesser extent (15%), suggesting that not all HVR1-specific antibodies are absolutely isolate-specific. Antibodies directed against individual variants of HVR1 were found in sera obtained early postinfection (p.i.) (< or = 1 year) but also in sera obtained several years later. An in vitro binding assay of HCV to tissue culture cells was employed to further characterize these sera. Five of seven sera that were obtained early p.i. prevented binding of HCV to cells. Preincubation of such sera with HVR1-specific fusion proteins restored binding of HCV to cells in four of five sera. These findings suggest that the majority of neutralizing antibodies are directed against HVR1.     

Dynamics of viral replication in infants with vertically acquired human immunodeficiency virus type 1 infection

About one-third of vertically HIV-1 infected infants develop AIDS within the first months of life; the remainder show slower disease progression. We investigated the relationship between the pattern of HIV-1 replication early in life and disease outcome in eleven infected infants sequentially studied from birth. Viral load in cells and plasma was measured by highly sensitive competitive PCR-based methods. Although all infants showed an increase in the indices of viral replication within their first weeks of life, three distinct patterns emerged: (a) a rapid increase in plasma viral RNA and cell-associated proviral DNA during the first 4-6 wk, reaching high steady state levels (> 1,000 HIV-1 copies/10(5) PBMC and > 1,000,000 RNA copies/ml plasma) within 2-3 mo of age; (b) a similar initial rapid increase in viral load, followed by a 2.5-50-fold decline in viral levels; (c) a significantly lower (> 10-fold) viral increase during the first 4-6 wk of age. All infants displaying the first pattern developed early AIDS, while infants with slower clinical progression exhibited the second or third pattern. These findings demonstrate that the pattern of viral replication and clearance in the first 2-3 mo of life is strictly correlated with, and predictive of disease evolution in vertically infected infants.     

Evaluation of hepatitis B and C viral markers: clinical significance in Asian and Caucasian patients with hepatocellular carcinoma in the United States of America

In order to evaluate the roles of hepatitis B virus (HBV) and hepatitis C virus (HCV) and their clinical significance in Asian-American and Caucasian patients with hepatocellular carcinoma (HCC) in the USA, 110 HCC patients, seen in a community-based teaching hospital in the Los Angeles area over a 10 year period, were enrolled. Seventy-nine (72%) patients were Asian-American and 31 (28%) were Caucasians. Of the 110 HCC patients, 69 (63%) were positive for serum hepatitis B surface antigen (HBsAg), 26 (24%) were positive for serum antibody to hepatitis C virus (anti-HCV), five (all Asian-Americans) were positive for both markers; 11 (10%) patients had a history of alcoholism. HBsAg was detected in 63 (80%) Asian-American patients, significantly higher than in the six (19%) Caucasian HCC patients (P < 0.01). Anti-HCV was detected in 10 (32%) Caucasian and in 16 (20%) Asian-American HCC patients (P > 0.05). Among Asian-American HCC patients, anti-HCV was more prevalent in those who were HBsAg-negative than in the HBsAg-positive patients (69 vs 8%; P < 0.01). A history of alcoholism was obtained in nine (29%) Caucasian HCC patients, significantly higher than in the two (3%) Asian-American HCC patients (P < 0.05). Comparing HCC patients with positive HBsAg and with anti-HCV, HBsAg-positive HCC patients were younger, Asian-Americans and predominantly male; 38% had a family history of liver disease. In contrast, anti-HCV-positive HCC patients were older by nearly a decade and 46% had a history of blood transfusion. Using a stepwise logistic regression analysis, Asian race and patient age < 50 years were found to be independent predictors for HBsAg-positivity, while a history of blood transfusion was the only predictor for anti-HCV-positivity in HCC patients. There was no significant difference in the rate of cirrhosis, serum levels of alpha-fetoprotein and survival between HBsAg-positive and anti-HCV-positive HCC patients. In conclusion, chronic HBV infection was the major aetiological factor in Asian-American HCC patients, while chronic HCV infection and alcoholism were major aetiological factors in Caucasian HCC patients in the USA.     

Long-term follow-up of a patient with hepatocellular carcinoma associated with triple hepatitis virus (HBV, HDV, HCV) infection

OBJECTIVE: To determine the serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin) in patients with systemic sclerosis (SSc). METHOD: Serum samples from 80 patients with SSc and 20 healthy control subjects were examined by a sensitive enzyme-linked immunosorbent assay. RESULTS: The serum levels of sVCAM-1 and sE-selectin were significantly higher in the patients with SSc than in the healthy controls. The serum levels of sVCAM-1 were correlated with the presence of pulmonary fibrosis, joint involvement and elevated erythrocyte sedimentation rate levels. The serum levels of sE-selectin were correlated with the presence of pulmonary fibrosis. CONCLUSION: These results suggest that endothelial activation is involved in the development of this disease.     

GB virus C/hepatitis G virus infection among patients with hepatocellular carcinoma in the inshore area of the Yangtze River, China

The latest meeting of the AAMC's Forum on the Future of Academic Medicine, on April 29, 1998, opened with a talk by Francis S. Collins, MD, PhD, director of the National Human Genome Research Institute, who reviewed the significant progress that the Human Genome Project (HGP) has made and speculated on how genetic discoveries and technologies would transform health-related research and ultimately the practice of medicine. The HGP's findings will offer clear improvements in diagnosis and prevention, and eventually in treatments, and the relationship between the academic medical center and the pharmaceutical industry will change--but remain good--as that industry applies the findings of the HGP. He stressed the need for the public and health care providers to develop a greater understanding of genetic issues, and urged changes in medical education to accomplish this. Forum members and Dr. Collins discussed the ethics and economics in patient care resulting from genetic research; forum members also asked whether academic medical centers could profit from genetic research findings. The second speaker was John Eisenberg, MD, administrator of the Agency for Health Care Policy and Research, which fosters health care research and disseminates to clinicians and others the findings of such research. Among other topics, Dr. Eisenberg described the new emphasis on health care outcomes and quality and described how his agency promotes research in these areas. Forum members asked who would pay for the information systems needed to communicate the findings of health services research and also noted that there is an expanding definition of health that places new pressures on already stressed academic medical centers, their missions, and their curricula, which must change. Michael Whitcomb, MD, of the AAMC, noted that the view that medical schools can't change their curricula has been proved wrong, and that 24 medical schools are working with the AAMC's Medical Schools Objectives Project on curricular reform. The forum closed with discussion of a few broader issues affecting academic medical centers.     

ECK, a human EPH-related gene, maps to 1p36.1, a common region of alteration in human cancers

Mouse eck, a member of the EPH gene family, has been mapped to mouse chromosome 4. The syntenic relationship between this chromosome and human chromosome 1 suggests that the human ECK gene maps to the distal short arm of human chromosome 1 (1p). Since this region is frequently deleted or altered in certain tumors of neuroectodermal origin, it is important to define the specific chromosomal localization of the human ECK gene. PCR screening of a rodent-human somatic cell hybrid panel by ECK-specific primers showed that ECK is indeed localized to human chromosome 1. Additional PCR screening of a regional screening panel for chromosome 1p indicated that ECK is localized to 1p36, distal to FUCA1. Furthermore, fluorescence in situ hybridization analysis with an ECK-specific P1 clone showed that ECK maps proximal to genetic marker D1S228. Taken together, the data suggest that ECK maps to 1p36.1, a region that is frequently deleted in neuroblastoma, melanoma, and other neuroectodermal tumors.     

Comparative study of expression of p21 and c-myc protein in hepatocellular carcinoma with pericarcinomatous liver tissue]

A new 2H/1H and 18O/16O equilibration device was tested, standardized and employed for the determination of total energy expenditure. It was shown that overweight men and women have increased resting metabolic rate as well as increased total energy expenditure when compared to their lean counterparts. The physical activity level (PAL)index was slightly decreased which possibly suggests a decreased physical activity in obese people.