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Biomedical subjects

M C Kew

Publications and source records attributed to M C Kew.

At least 55 records · Page 3Linked to original sources
PubMed1996

Kaposi's sarcoma-associated herpesvirus in Kaposi's sarcoma occurring in immunosuppressed renal transplant recipients.

Kaposi's sarcoma-associated herpesvirus (KSHV) has been implicated in the genesis of Kaposi's sarcoma and other tumors occurring in immunosuppressed individuals. Using amplification by the polymerase chain reaction and nucleotide sequencing of extracted DNA, we have detected the KS330(233) sequence of KSHV DNA in Kaposi's sarcoma tissue from 4 immunosuppressed renal transplant recipients. The sequences shared a greater than 98% homology with those described in KSHV DNA from Kaposi's sarcoma in patients with acquired immunodeficiency syndrome. In another 2 renal transplant recipients KSHV DNA could not be detected in scar tissue at the site of previous Kaposi's sarcoma that had resolved after immunosuppression was discontinued and haemodialysis recommenced. These findings support the hypothesis that KSHV may be the infectious agent concerned in the genesis of Kaposi's sarcoma.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Use of NS-4 peptides to identify type-specific antibody to hepatitis C virus genotypes 1, 2, 3, 4, 5 and 6.

The 5' end of the NS-4 protein of different genotypes of hepatitis C virus (HCV) is highly variable in nucleotide and inferred amino acid sequence, with frequent predicted amino acid substitutions between all six of the major HCV genotypes described to date. This region has been shown to be antigenic by epitope mapping, and elicits antibody in HCV-infected individuals with a detectable type-specific component. We have used this sequence data to specify branched peptides for an indirect binding/competition assay to detect type-specific antibody to each major genotype. A total of 183 out of 210 samples (87%) from blood donors and patients with chronic hepatitis C infected with genotypes 1 to 6 showed detectable type-specific antibody to NS-4 peptides that in almost all cases (> 97 %) corresponded to the genotype detected by a PCR typing method. These findings demonstrate the existence of major antigenic differences between genotypes of HCV, and indicate how infection with different variants of HCV may be detected by a serological test.

Amino Acid Sequence↗
PubMed1995

An outbreak of hepatitis A among South African patients with hemophilia: evidence implicating contaminated factor VIII concentrate as the source.

We report an outbreak of hepatitis A in nine South African hemophiliacs treated exclusively with infusions of factor VIII concentrate. The solvent/detergent (S/D) method (which does not inactivate nonenveloped viruses) was used for virus eradication. In three of six patients studied at a molecular level hepatitis A virus (HAV) complementary DNA (cDNA) amplified from serum by reverse transcription-polymerase chain reaction (RT-PCR) was identical to HAV cDNA in 1 of 14 lots (no. 53) of factor VIII tested. The plasma for lot 53 was obtained from donors in the United States: 1 of 12 samples of this source material contained the same HAV cDNA sequences. In another two patients receiving lot 53, the degree of identity between HAV cDNA in serum and that in factor VIII was only 88% and 89%, respectively, and in the sixth patient, who did not receive lot 53, it was 90%. The degree of HAV cDNA homology among five patients in an independent point-source outbreak of hepatitis A was 100%, and that in nine patients who acquired this infection sporadically in Johannesburg, Egypt, or Russia, was 93% to 100%. Whether the three hemophiliacs with low HAV cDNA homology with lot 53 acquired the infection from other unidentified virus strains contaminating factor VIII or from extraneous sources is unknown. This study provides further evidence that factor VIII concentrate prepared by the S/D method may be contaminated by the HAV, in this instance at source, and may cause hepatitis in recipients. Proof of a cause-and-effect relationship will, however, depend on animal inoculation studies.

Adolescent↗
PubMed1995

Hepatitis C virus infection in black patients with hepatocellular carcinoma in southern Africa.

Chronic hepatitis C virus (HCV) infection is implicated in the etiology and pathogenesis of a relatively small proportion of hepatocellular carcinomas (HCC) in black residents of southern Africa. The major risk factor for the tumor in this population is chronic hepatitis B virus (HBV) infection acquired early in life. Only 13.2% of black patients with HCC are currently infected with HCV (as judged by the presence of HCV RNA in serum) alone, and another 4.3% are infected with both HCV and HBV. Antibody to HCV can be detected with second generation assays in 19.5% of HCC patients. Fifty percent of the HCC patients have only current HBV infection and a further 35.9% show markers of past HBV infection (including 9.1% who also are currently infected with HCV). The prevalence of current HBV infection is significantly lower in HCV RNA-positive than in HCV RNA-negative patients, and this difference is independent of the sex, age, or geographical location of the patients. Only 5.4% of HCC patients are not infected with either HBV or HCV. Patients with HCV-associated HCC are appreciably older than those with tumors not associated with HCV and those with tumors associated with HBV, and the differences are independent of geographical location of the patients. Patients with HCV-associated HCC are more likely to be urban dwellers and less likely to be rural dwellers than are those with HBV-related tumors. Differences in sex distribution and alpha-fetoprotein levels just fail to reach statistical significance between patients with HCV-related and HBV-related HCC. The pathogenesis of HCV-related HCC in black Africans, as in all populations, is uncertain. A direct carcinogenic effect appears unlikely, and the available evidence favors an indirect effect mediated via chronic necroinflammatory hepatic disease. Because very few of our patients undergo surgery or have a necropsy performed, the relationship between HCV-associated HCC and cirrhosis in black Africans has not been analyzed.

Black People↗
PubMed1994

Enhancement of HBsAg detection in serum of patients with chronic liver disease following removal of circulating immune complexes.

Patients with chronic liver disease and hepatocellular carcinoma may lack serological evidence of previous hepatitis B virus infection. The purpose of the present study was to test the hypothesis that circulating immune complexes may interfere with the detection of low levels of HBsAg in such patients. Sera from 190 patients were initially screened for the presence of circulating immune complexes. Patients belonged to three clinical categories: asymptomatic HBsAg carriers (50 patients), chronic liver disease (30 patients) and hepatocellular carcinoma (110 patients). Forty-one of the group of 190 patients (21%) were positive for circulating immune complexes. Sera from 21 patients were selected for further evaluation. The sera of 13 chronic liver disease or hepatocellular carcinoma patients (HBsAg negative, hepatitis B virus-DNA negative, with or without evidence of previous hepatitis B virus infection) and eight HBsAg positive carriers (four asymptomatic, three with chronic liver disease and one with hepatocellular carcinoma) were passed through a Clq affinity column (first column) to remove circulating immune complexes. Unbound material was then passed through a monoclonal IgG2a anti-HBs affinity column (second column). Unbound material (following both columns) contained free HBsAg, as determined by monocolonal radio-immunoassay, in eight patients in whom HBsAg had been undetectable in the original serum. Removal of circulating immune complexes from the serum of the three HBsAg positive patients with chronic liver disease also caused a significant increase in measurable circulating HBsAg compared with the original serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

A comparative study on hepatocellular carcinoma between South Africans and Japanese from the viewpoint of nuclear DNA content.

Nuclear deoxyribonucleic acid (DNA) content of hepatocellular carcinoma (HCC) in 41 South African and 47 Japanese patients at autopsy was analysed by dual-wavelength microspectrophotometry. The DNA distribution patterns were classified as type I, II, III or IV and as low ploidy (types I, II) or high ploidy (types III, IV), according to the degree of dispersion. We found a significantly higher incidence of high ploidy in South African HCC than in Japanese HCC. Moreover, type IV was significantly more frequent among South Africans than among the Japanese. These findings demonstrate that large differences in biological characteristics and clinical behaviour of HCC between South Africa and Japan may reflect differences in DNA distribution patterns which we observed between these two races.

Adolescent↗
PubMed1994

The seroepidemiology of hepatitis A virus infection in South African Chinese people.

The age-specific prevalence of antibody to hepatitis A virus (anti-HAV) was determined in 949 Chinese people residing in South Africa in 1983-1985. This small community is comprised of original settlers from the mainland China province of Guandong, where hepatitis A virus infection is endemic, and their South African-born descendants. The overall anti-HAV prevalence (by radioimmunoassay) in South African Chinese people was 57.8%, was lowest in children aged 0-9 and 10-19 years (10.0% and 12.8%, respectively), and rose progressively with increasing age to a peak level of 96.6% in the sixth decade of life. A sharp rise in antibody prevalence to 82.9% was observed in the 30-39 year age group, suggesting a high level of childhood exposure at a time of socioeconomic development in South Africa. The age-specific prevalences of anti-HAV among young South African Chinese people are appreciably lower than those of mainland Chinese children, the majority of whom are infected by age 19 or 20 years. Their rates of infection are also much lower than those for Black South African children living under adverse sanitary conditions. This study indicates that a large proportion of South African Chinese children and adolescents are susceptible to HAV infection and should be included in a broader national vaccination programme.

Adolescent↗
PubMed1994

Hepatitis C virus and hepatocellular carcinoma.

In the short time that the hepatitis C virus has been known to be the major cause of parenterally acquired non-A, non-B hepatitis, it has become increasingly apparent that chronic infection with this virus is closely associated with the occurrence of hepatocellular carcinoma. Evidence for the link is provided mainly by case/control studies and case series but also by longitudinal studies. The proportion of patients with hepatocellular carcinoma who have circulating antibody to hepatitis C virus shows a pronounced geographical variation. In Japan, Spain, and Italy antibody is present in 47-83% of the patients, with relative risks of 52 (95% confidence interval 24-114) in Japanese and 69 (15-308) in Italian carriers of the virus. In regions where hepatitis B virus infection is endemic and is the major risk factor for hepatocellular carcinoma, antibody to hepatitis C virus is present in the serum of a smaller proportion (6-39%) of patients, with relative risks of 7 (1.6-39) in Taiwan and 6 (0.5-69) in Senegal. Comparatively low prevalences (13-35%) have also been recorded in the remaining geographical regions for which information is available, with relative risks of 10.4 (4-26) in Greece and 10.5 (3.5-31) in North America. There is some evidence for an interaction between hepatitis C and B viruses in hepatocellular carcinogenesis, but this remains to be proved. In most populations hepatocellular carcinoma develops at an older age in patients with hepatitis C virus-induced tumours than in those with hepatitis B virus-induced tumours. The pathogenesis of hepatitis C virus-related hepatocellular carcinoma is unknown. Because it always arises in association with cirrhosis or chronic hepatitis and because there is no evidence that the virus is directly carcinogenic, it appears that hepatitis C virus induces malignant transformation indirectly by causing chronic necroinflammatory hepatic disease which in turn is responsible for tumour formation.

Adolescent↗
PubMed1993

Mutant woodchuck hepatitis virus genomes from virions resemble rearranged hepadnaviral integrants in hepatocellular carcinoma.

Although hepadnaviruses are implicated in the etiology of hepatocellular carcinoma, the pathogenic mechanisms involved remain uncertain. Clonally propagated integrations of hepadnaviral DNA into cellular DNA can be demonstrated in most virally induced hepatocellular carcinomas. Integration occurs at random sites in cellular DNA, but the highly preferred sites in viral DNA are adjacent to the directly repeated sequence DR1, less often DR2, or in the cohesive overlap region. Integrants invariably contain simple deletions or complex rearrangements that have been thought to occur after integration. We report here the detection of mutant woodchuck hepatitis virus (WHV) genomes cloned from virions in serum that are strikingly similar to the rearranged hepadnaviral genomes found previously as integrated sequences in cellular DNA. Of 102 cloned genomes studied, 2 had large inverted duplications, 1 a 219-nucleotide direct duplication, and 1 a 219-nucleotide deletion. Virus-virus DNA junctions occurred either adjacent to DR1 or DR2 or in the cohesive overlap region at preferred topoisomerase I cleavage sites. Since these sites are located in the single-stranded regions of the genome, cleavage by topoisomerase I would produce linear molecules that would be expected to be highly recombinogenic since this enzyme, possessing nicking and ligating activities, would remain covalently attached. Sucrose density gradient centrifugation coupled with polymerase chain reaction studies confirmed that the mutant WHV DNA forms resided in virions and did not represent free viral DNA released from infected cells or were unlikely to be an artifact of the cloning process. Thus, the finding in virions of mutant WHV DNA similar to WHV DNA integrated into cellular DNA suggests that the processes of mutation and integration are linked in some instances. Furthermore, the mutant genomes that are preferentially integrated into cellular DNA may have an etiologic role in hepatocarcinogenesis.

Animals↗
PubMed1993

Hepatitis C virus RNA in southern African blacks with hepatocellular carcinoma.

We used a sensitive and specific cDNA polymerase chain reaction assay to detect hepatitis C virus (HCV) RNA in serum samples from 128 unselected southern African Blacks with hepatocellular carcinoma (HCC) and found HCV RNA in 26 (20.3%) of these patients. Antibodies to HCV (anti-HCV) were detected in 59 patients (46.1%) with a first-generation ELISA test, and only 19 of these patients were HCV RNA-positive. Anti-HCV was detected in 25 patients (19.5%) with a second-generation ELISA test, and 17 of these patients were HCV RNA-positive. Among the second-generation ELISA- and HCV RNA-positive patients, 14 were anti-HCV positive, 2 were indeterminate, and 1 was anti-HCV negative in a second-generation recombinant immunoblot assay, whereas all patients who were second-generation ELISA positive, but HCV RNA negative, were anti-HCV negative in this immunoblot assay. A total of 5 patients were negative in both ELISA tests but were HCV RNA positive. Seventy-one patients (55.5%) had evidence of a current HBV infection, 50 (39.1%) had evidence of a previous infection, and 7 (5.5%) had no evidence of a current or previous HBV infection. The prevalence of current HBV infection was significantly lower in patients who were positive for HCV RNA than in those who were negative (P = 0.001). This difference was not dependent on sex, age, or geographical location of the patients. The mean age of HCC patients positive for HCV RNA (52.3 years) was significantly higher (P < 0.001) than that of negative patients (40.3 years), and the difference was not dependent on HBV status or geographical location. Patients positive for HCV RNA were more likely to be urban than were negative patients. Thus, a significant number of southern African Blacks with HCC had a current HCV infection but not a current HBV infection, further suggesting that infection with HCV plays a role, albeit minor, in the development of HCC in this population.

Adult↗
PubMed1993

Heterogeneity of the woodchuck hepatitis virus genome in a chronically infected woodchuck.

The nucleotide sequence of an isolate of woodchuck hepatitis virus (WHV) from the serum of a woodchuck trapped in New York state (WHVNY) was compared with the sequences of previously published isolates. The nucleotide sequence of WHVNY was closest to that of an isolate originating from New Jersey: the two genomes shared a 15 nucleotide in-frame deletion in the region where the presurface and polymerase genes overlap (nucleotides 3260-3274) and differed by 54 point mutations (1.6% of genome). Amino acid differences ranged from 0.4% in the surface gene to 5.7% in the X gene. Three isolates from woodchucks that originated in Pennsylvania and Maryland did not contain the deletion and differed from WHVNY by 102 to 106 point mutations (3.0% to 3.2% of nucleotides). Amino acid changes ranged from 0.5% in the core gene to 5.7% in the X-gene. Thus, WHVNY differed little from previous isolates. Next, the genomes from 102 independent clones of WHVNY were compared to ascertain the extent of sequence variation among WHV genomes in a chronically infected animal. A total of 98 clones had genomes of unit length while 2 clones had genomes shorter than unit length and 2 clones had genomes longer than unit length. The clones not of unit length possessed deletions or inverted duplications of sequence. The rate of mutation in the viral genes was 2.65 mutations per 10,000 nucleotides in the precore domain, 1.27 per 10,000 in the X-gene, 0.98 per 10,000 in the presurface gene, and 3.77 per 10,000 at the 5' end of the core gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1992

Alcohol consumption as a risk factor for hepatocellular carcinoma in urban southern African blacks.

Our purpose was to ascertain whether alcohol abuse is a risk factor for the development of hepatocellular carcinoma in urban southern Africa blacks and, if so, to relate alcohol consumption to other possible risk factors such as persistent hepatitis-B-virus infection, smoking, male sex, in this subpopulation. A prospective, hospital-based, case-control format involving 101 patients with hepatocellular carcinoma and 101 controls was used. The mean age of the patients was 53.7 +/- 1.85 years and the male:female ratio 3.2:1. An increased risk was found, but only in urban men over the age of 40 years who habitually drank more than 80 g of ethanol daily. The risk remained after adjusting for chronic hepatitis-B infection, smoking, and sex (odds ratio 4.4, 95% confidence interval 1.3 to 16.6; p = 0.003). Smoking proved not to be a risk factor, either alone or in concert with alcohol consumption. Hepatitis-B infection was confirmed as a major risk in younger men and in women, but in urban men over the age of 40 years alcohol abuse was a greater risk. Current hepatitis-B infection and alcohol abuse were additive risks.

Adult↗
PubMed1992

The precore gene of the woodchuck hepatitis virus genome is not essential for viral replication in the natural host.

A number of naturally occurring hepatitis B virus mutants that cannot synthesize the virus precore protein have been identified. Such mutants have been associated with more severe forms of hepatitis, including fulminant hepatitis. The most common mutation observed is a substitution of G to A in the distal precore gene that converts a codon specifying Trp (TGG) to a termination codon (TAG). Using oligonucleotide-directed mutagenesis, we have produced the same point mutation in the precore gene of an infectious clone of woodchuck hepatitis virus (WHV). Transfection of mutant WHV DNA into the livers of adult woodchucks resulted in replication of the mutant in three of three susceptible animals. Levels of virus replication and transient elevations in liver enzymes in serum were similar to those of adult animals infected with wild-type WHV. Virions, found to possess mutant precore genes by polymerase chain reaction amplification and DNA sequencing, were recovered from the serum of one of the animals and inoculated subcutaneously into neonatal woodchucks. They produced infection in all five animals studied. The level of virus replication in neonatal animals infected with this mutant virus was comparable to that found in neonatal woodchucks infected with wild-type WHV, but none of five woodchucks infected with the precore mutant virus as neonates became chronic virus carriers. It was concluded that the precore gene of the WHV genome is not essential for virus replication in the natural host but may be important for chronic infection.

Animals↗
PubMed1992

Tumours of the liver.

One of the major debates in hepatocellular carcinogenesis at present is whether the hepatitis-B and -C viruses are directly carcinogenic or exert their effect indirectly by causing chronic necro-inflammatory hepatic disease, which in turn is responsible for malignant transformation of hepatocytes. This debate has been fueled by the observation that hepatitis C virus is a single-stranded RNA virus with no precedent for inducing cancer but with a marked propensity to cause chronic necro-inflammatory hepatic disease and by the findings in Chisari's transgenic mouse model, which suggest that severe and prolonged hepatocellular injury per se induces a proliferative response that progresses to tumour formation. Recent reports of a guanine to thymine mutation of the third base of codon 249 of the tumour suppressor gene, p53, in 50% of patients with hepatocellular carcinoma in regions of high aflatoxin exposure, and mutagenic experiments showing that aflatoxin B1 binds particularly to guanine residues in G-C-rich domains and that codon 249 is a preferred target have suggested a mechanism whereby aflatoxin might induce malignant transformation.

Aflatoxins↗
PubMed1991

Integration of hepatitis B vaccination into rural African primary health care programmes.

OBJECTIVE: To determine the efficacy of hepatitis B vaccine when added to the routine expanded programme on immunisation under field conditions in rural Africa. DESIGN: Infants were immunised according to two schedules--an early schedule at birth, 3 months, and 6 months and a later schedule to correspond with routine vaccination in the expanded programme on immunisation at 3 months, 4 1/2 months, and 6 months. SETTING: Venda, northern Transvaal, South Africa, a self governing region of 7460 square kilometers varying from rural villages to small towns. SUBJECTS: The 1989 birth cohort of Venda. MAIN OUTCOME MEASURES: Coverage for hepatitis B vaccine at first, second, and third doses; serological assessment of vaccine efficacy by prevalence of antibodies to hepatitis B surface antigen in infants who had completed the three dose course of immunisation; antibodies to hepatitis B core antigen to determine if natural infection occurred. RESULTS: Vaccine coverage for hepatitis B dropped sharply from 99% to 53% to 39% for the first, second, and third dose respectively. In contrast, vaccine coverage was maintained at 97-99% for the three doses of poliomyelitis vaccine. Serological evaluation of vaccine efficacy showed that only 3.5% of recipients of all three doses failed to develop antibodies to hepatitis B surface antigen. Only 6.6% of vaccine recipients were vaccinated according to either the early or later schedules whereas 93.4% received their doses of vaccine at intervals beyond the limits of either of the planned schedules. There was, however, no significant difference in seroconversion to the surface antigen between the "unscheduled" or scheduled groups of those who were vaccinated according to the early or late schedules. The pattern of prevalence of antibodies to hepatitis B core antigen, which showed a sharp fall in children aged over 7 months, suggested that the antibodies were acquired passively rather than by active infection. CONCLUSIONS: Supplementation of the present expanded programme on immunisation with hepatitis B vaccine in rural Africa is fraught with difficulties. However, the vaccine was effective within a fairly wide spacing of dosage. Adding hepatitis B vaccine to diphtheria, tetanus, and pertussis as a tetravalent vaccine is proposed as a means of effectively integrating it into the expanded programme on immunisation in Third World settings.

Developing Countries↗