Alpha-fetoprotein glycosylation is abnormal in some hepatocellular carcinoma, including white patients with a normal alpha-fetoprotein concentration.

Lectin-affinity analyses with Lens culinaris agglutinin (LCA) and other lectins have demonstrated that the glycosylation of alpha-fetoprotein (AFP) secreted by hepatocellular carcinomas (HCC) is frequently altered when the serum AFP concentration is increased. To determine if AFP LCA-binding properties are altered in patients with HCC whose serum AFP concentration is normal, the percentage of LCA-binding AFP in serum from white newborns, white normal adults, white patients with chronic hepatitis and hereditary tyrosinemia and white and black patients with HCC were determined. The serum LCA-binding AFP fraction was low in newborns (1-4%) and normal adults (1-8%). There was a significant increase in LCA-binding AFP in patients with chronic hepatitis (10-24%) and hereditary tyrosinemia (5-35%). The AFP LCA-binding fraction was clearly abnormal (greater than 40%) in three of the white patients with an HCC and a normal serum AFP concentration, and the range of values (10-63%) in these HCC patients was similar to that seen in both white and black patients with HCC accompanied by increased AFP concentrations.

Persistent hepatitis B virus infection and hepatoma in The Gambia, west Africa. A case-control study of 140 adults and their 603 family contacts.

To determine the incidence of persistent hepatitis B virus infection and its etiologic role as a cause of hepatoma, the authors carried out a case-control investigation of 70 persons with hepatoma, 70 controls, and their families in 1981-1982 in The Gambia, West Africa. The risk of developing hepatoma after the age of 39 years was 1.4% in men and 0.3% in women. Hepatoma occurred more than twice as frequently among persons who had four or more older siblings as among persons who had less than two older siblings. The attributable risk between persistent infection with hepatitis B virus and hepatoma was 78% for individuals aged less than 50 years and 37% for persons aged 50 years or more, with an overall risk of 53%. The high prevalence of hepatitis B surface antigen and hepatitis B e antigen antigenemia in children under 15 years of age (14% of 341 children) and the positive correlation between late birth order and risk of developing hepatoma suggest that postnatal early childhood exposure to hepatitis B virus is an important risk factor. The use of a hepatitis B virus vaccine which provides durable immunity in very young children will probably prevent most cases of hepatoma.

Failure to isolate human T cell lymphotropic virus type I and to detect variant-specific genomic sequences by polymerase chain reaction in Melanesians with indeterminate western immunoblot.

The controversy over the endemicity of human T cell lymphotropic virus type I (HTLV-I) in Melanesia has been settled recently by the isolation of genetically distinct, highly divergent sequence variants of HTLV-I from unrelated inhabitants of Papua New Guinea and the Solomon Islands. Still at issue, however, is the significance of the high frequency of indeterminate HTLV-I Western blots (defined as reactivity to only gag-encoded proteins) among Melanesians. To investigate whether this indeterminate seroreactivity reflects specific reactivity to the Melanesian HTLV-I variants, 27 seroindeterminate Melanesians from Papua New Guinea and the Solomon Islands were studied for evidence of HTLV-I infection. Although antibodies against Melanesian variant-specific env gene products and variant-specific env gene sequences were detected by Western blot analysis and polymerase chain reaction, respectively, in all 11 HTLV-I Western blot-positive Melanesians, none of the 27 seroindeterminate Melanesians had such variant-specific antibodies or HTLV-I proviral sequences. In addition, attempts to isolate HTLV-I from seroindeterminate individuals were unsuccessful. These data indicate that HTLV-I infection is not the cause of the indeterminate Western blot reactivity seen in Melanesia.

Comparison between strains of human T lymphotropic virus type I isolated from inhabitants of the Solomon Islands and Papua New Guinea.

Strains of human T lymphotropic virus type I (HTLV-I) isolated from T cell lines (SI-1, SI-3, and SI-5) from three individuals in separate regions of the Solomon Islands were compared with a variant (PNG-1) isolated from a healthy person in Papua New Guinea and a prototype strain from Japan (MT-2). The SI-1, SI-3, and SI-5 cell lines were predominantly CD8+. Expression of gag- and env-encoded virus-specific proteins was detected in SI-1, SI-3, and SI-5 and in MT-2 cells by immunofluorescence and Western immunoblot; gag proteins p19 and p24 were absent in PNG-1 cells. HTLV-1 gag and pol gene sequences were detected in DNA extracted from SI-1, SI-3, and SI-5 cells by polymerase chain reaction; env sequences were not found in SI-5 cells. Genomic Southern analysis of PstI digests of SI-1, SI-3, and SI-5 DNA exhibited the three moderate-sized fragments typical of prototype HTLV-I. By contrast, PstI digests of PNG-1 DNA yielded two larger fragments.

Highly divergent molecular variants of human T-lymphotropic virus type I from isolated populations in Papua New Guinea and the Solomon Islands.

To determine the molecular genetic relationship between Melanesian strains of human T-lymphotropic virus type I (HTLV-I) and cosmopolitan prototype HTLV-I, we amplified by PCR, then cloned, and sequenced a 522-base-pair region of the HTLV-I env gene in DNA extracted from uncultured (fresh) and cultured peripheral blood mononuclear cells obtained from six seropositive Melanesian Papua New Guineans and Solomon Islanders, including a Solomon Islander with HTLV-I myeloneuropathy. Unlike isolates of HTLV-I from Japan, the West Indies, the Americas, and Africa, which share greater than or equal to 97% sequence homology, the Melanesian strains of HTLV-I were only 91.8%-92.5% identical with a prototype Japanese HTLV-IATK-1. The nucleotide sequence of proviral DNA from the Solomon Islander with HTLV-I myeloneuropathy also diverged markedly from that of HTLV-I isolated from Japanese patients with HTLV-I-associated myelopathy and from Jamaican patients with tropical spastic paraparesis, suggesting that these variant viruses are capable of causing disease. The HTLV-I variants from Papua New Guineans, in turn, differed by nearly 4% from the Melanesian variants from Solomon Islanders, indicating the existence of another HTLV-I quasi-species. By contrast, HTLV-I strains from two residents of Bellona Island, a Polynesian Outlier within the Solomon Islands, were closely related to cosmopolitan prototype HTLV-I (greater than or equal to 97% sequence identity), suggesting recent introduction, possibly during this century. These findings are consistent with a proto-Melanesian HTLV-I strain of archaic presence, which evolved independently of contemporary cosmopolitan strains, and pose new questions about the origin and global dissemination of HTLV-I.

Verification of HTLV-I infection in the Solomon Islands by virus isolation and gene amplification.

We report the detection of human T-lymphotropic virus type I (HTLV-I) genomic sequences by polymerase chain reaction in lymphocyte cultures of three unrelated native Solomon Islanders, including a patient with HTLV-I myeloneuropathy, residing in widely separated regions. In addition, we have isolated HTLV-I from T-cell lines derived from two of these individuals. Virus-specific proteins of 15, 19, 24, 46 and 53 kilodaltons were detected by immunofluorescence and Western immunoblot, using serum from a Colombian patient with HTLV-I myeloneuropathy, sera from HTLV-I-infected rabbits, and monoclonal and polyclonal antibodies against HTLV-I gag and env gene products. Amplification of HTLV-I gag, pol and env sequences by polymerase chain reaction confirmed that the viral isolates were HTLV-I, not HTLV-II. Our data clearly demonstrate that HTLV-I does exist in Melanesia. Although the Solomon Islands viral isolates resemble prototype strains of HTLV-I, we believe they represent variants of HTLV-I, particularly in the light of our recent isolation of an HTLV-I variant from Papua New Guinea. Nucleotide sequence analysis of these viral strains, now in progress, should clarify the molecular epidemiology and phylogeny of HTLV-I.

Human T-lymphotropic virus type I infection in the Solomon Islands.

To ascertain the prevalence of human T-lymphotropic virus type I (HTLV-I) infection and the occurrence of diseases caused by HTLV-I in the Solomon Islands, we tested 1141 sera from 851 patients (317 females and 534 males), who were hospitalized at the Central Hospital in Honiara between February 1984 and November 1988, for antibodies to HTLV-I using an enzyme-linked immunosorbent assay (ELISA). Sera from 69 of 81 ELISA-positive patients and from 56 ELISA-negative patients were then tested by Western analysis. As verified by strict Western immunoblot criteria, the overall HTLV-I seroprevalence was 2.2% (19/851). Age- and gender-specific prevalence data indicated an age-related acquisition of infection with no sexual predominance. No diagnosis category was over-represented among the seropositive patients. HTLV-I-specific antibodies were found in serum and cerebrospinal fluid samples from one of six patients with spastic paraparesis. As in other Melanesian populations, the majority of ELISA-positive sera could not be confirmed by Western analysis. Reactivity to three or more gag-encoded proteins was found in 85% (45/53) of ELISA-positive, Western blot-indeterminate sera, and 30% (16/53) reacted to p19 and an env gene product but lacked reactivity to p24. Whether or not the high frequency of indeterminate HTLV-I Western immunoblots in the Solomon Islands is indicative of incomplete specific reactivity to HTLV-I or the existence of antigenically related retroviruses is being investigated.

Serum tumor necrosis factor associated with malaria in patients in the Solomon Islands.

There is now significant evidence that tumor necrosis factor (TNF) is involved in the pathogenesis of malaria. We have tested sera from patients presenting with a febrile illness admitted to hospital in Honiara, Solomon Islands, for the presence of TNF, interferon-gamma, and interleukin-1 (IL-1). This study differs from previous reports as the subjects were mainly adults from a semi-immune population living in an endemic area. The results from 2 different commercially-available assays for TNF were compared, and one was found to be superior to the other. Serum TNF concentrations correlated with malarial parasite density and the patients' temperatures, but not with interferon or IL-1. The results are discussed in the context of the immunopathology of this disease.

An international and interregional comparison of haemostatic variables in the study of ischaemic heart disease. Report of a working group.

Levels of haemostatic variables that may be involved in thrombogenesis have been compared in groups of men of similar mean age in communities at very low (Gambia), high (England and Czechoslovakia) or very high (Scotland and Finland) risk of ischaemic heart disease (IHD). There was a consistent gradient of higher factor VII levels with higher IHD risk and also suggestive gradients in the case of two other vitamin K dependent factors, factors II and X. Mean platelet counts were lower and mean fibrinolytic activity was greater in Gambian men than in European men. There was a suggestive though not entirely consistent association between mean fibrinogen levels and IHD risk in the groups from IHD-endemic countries. The results as a whole, and particularly those on factor VII, strengthen the case for the increasingly detailed epidemiological as well as laboratory investigation of the role of the haemostatic system in thrombogenesis and IHD.

The diagnostic value of liver scanning in The Gambia.

A simple radioisotope scanner was used in a study of liver diseases in The Gambia. Scans were of value in localizing areas for biopsy or aspiration and in defining the liver in the presence of gross ascites. Although the scan was not helpful in diagnosis it provided a measure of the size of filling defects during treatment.

Racial differences in calcitonin and katacalcin.

Profound racial differences exist in the incidence of osteoporosis, particularly in women. To investigate possible underlying reasons for this, we have measured the circulating levels of calcitonin (iCT), a bone-protecting hormone, and its flanking peptide, katacalcin (iKC), in black Gambian and white British populations. Whilst sex differences in both peptides were observed, with males having higher levels than females, the most striking finding was that white women have the lowest iCT levels. This important observation may explain, at least in part, why osteoporosis is particularly a disease of white, postmenopausal women.

Hepatitis B surface antigen containing immune complexes occur in seronegative hepatocellular carcinoma patients.

IgG, IgM and hepatitis B surface antigen (HBsAg) containing immune complexes (IC) were detected by the Clq and conglutinin solid phase assays in both HBsAg+ and HBsAg- groups of patients with primary hepatocellular carcinoma (HCC). No differences were observed between the two patient groups either in the levels of antigen non-specific and HBsAg specific complexes or in the immunoglobulin isotype in the complexes. The results show that HBsAg can occur in an IC form in the sera of patients classified as HBsAg- by sensitive commercial assays and provides evidence of a further association of hepatitis B virus (HBV) and HCC in antigen negative patients. Furthermore, the HBsAg IC in HCC patients differ from those in other HBV infected subjects in that they are preferentially detected by the Clq assay.

Leishmaniasis in The Gambia. 3. Is its incidence increasing?

During 1982 a further case of visceral leishmaniasis and six cases of cutaneous leishmaniasis were seen at the Medical Research Council Laboratories in The Gambia, suggesting that the incidence of this infection in The Gambia is increasing.

Hepatitis B virus infection in two Gambian villages.

The prevalence of hepatitis B virus infection was markedly different in two neighbouring Gambian villages. 62% of children in Manduar aged 2-4 years were infected whereas in Keneba, the other village, only 27% of this age-group were infected. However, in both villages few infants were infected--none under 6 months of age and only 2 of 58 between the ages of 6 and 12 months. Carriage of hepatitis B surface antigen (HBsAg) was high, reaching a peak of 36% in the 5-9 age-group in Manduar and 17.6% in the 2-4 age-group in Keneba. 86% of all the children under the age of five who were HBsAg-positive also carried hepatitis B e antigen (HBeAg). This proportion fell to 17.6% for children aged 10-14 years and to 12.9% for mothers. Infection clustered in families, transmission from sib to sib being of major importance. The chances of a child being an HBsAg carrier were approximately 42% if an elder sib carried the antigen, 27% if either mother or father was a carrier, and 15% if neither mother or father was a carrier. There were 4 HBeAg-positive mothers who were highly infectious, since 10 of 11 of their children became HBsAg carriers. Carriage of surface antigen lasted many years; 63% of those carrying the antigen in 1972 were still positive in late 1980. 4 cases of primary hepatocellular carcinoma out of 672 adults have been diagnosed in the past five years. All 4 were in HBsAg carriers.

Hypertrophic hepatic osteoarthropathy. Clinical, roentgenologic, biochemical, hormonal and cardiorespiratory studies, and review of the literature.

Twenty patients with biopsy proved liver disease, and roentgenologic features of hypertrophic osteoarthropathy have been studied, and the literature has been reviewed. The syndrome is a rare association of many chronic liver diseases, including primary biliary cirrhosis, bile duct carcinoma, benign bile duct stricture, chronic active hepatitis, posthepatitic cirrhosis and alcoholic cirrhosis. Patients may be asymptomatic, although bone pain, arthralgia or arthritis may be presenting symptoms. Ninety per cent of the patients are clinical jaundiced at the time of diagnosis, and 95 per cent have digital clubbing. The distal tibia and fibula are the first bones to become involved, although wrist, foot bones, femurs, hand bones and humeri may be affected in order of frequency. There is no correlation between the presence of esophageal varices or surgical portacaval shunts and the extent of the syndrome, neither is there a correlation with the degree of liver function impairment. Serum calcium and phosphate levels are normal, as is urinary hydroxyproline and estrogen excretion. There was no evidence to implicate elevated levels of growth hormone or overdosage of vitamin A. Although the majority of patients tested had mild arterial hypoxemia, increased cardiac output and evidence of right to left shunting, these were also present in disease-matched control subjects without osteoarthropathy. For screening purposes, patients with chronic liver disease and clubbing should have roentgenologic studies of the lower tibias and fibulas, to select those patients suitable for a more extensive skeletal survey.