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BACKGROUND: Two neoplastic Kaposi's sarcoma (KS) cell lines, KS Y-1 (derived from a patient with KS associated with acquired immunodeficiency syndrome) and KS SLK (derived from an immunosuppressed patient with a renal transplant and KS or iatrogenic KS), have been shown to have abnormal chromosome constitution and to require no exogenous growth factors. They produce malignant tumors in immunodeficient mice. In contrast, all other cell cultures prepared in the past from KS specimens have shown to have normal diploid characteristics are hyperplastic, and depends on cytokines for growth, but they do not produce malignant tumors in immunodeficient mice. PURPOSE: We investigated whether the chromosomal changes that occurred in these KS cell lines were random contribute to the pathogenesis of KS. METHODS: We used the conventional G-banding technique and fluorescence in sti hybridization to identify structural and numerical chromosomal changes in the KS cell lines. RESULTS: We demonstrated that both cell lines are aneuploid and have some additional features in common, i.e., loss of copies of chromosomes 14 and 21 and nonrandom translocations and deletions in the short arm of chromosome 3 at region 3p14. These KS cell lines also exhibits loss of heterozygosity of loci at region 3p14-ter. CONCLUSION: This is the first time nonrandom chromosomal alterations have been described in KS neoplastic cells. On the basis of information available on other available on other cancers, the chromosome 3 alterations observed here can be expected to contribute to the neoplastic process in KS. IMPLICATIONS: Future research should focus on the identification cytogenetic markers, thus facilitating generation of specific molecular probes for detecting neoplastic cells early in the disease process.

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The possible causal association of human papilloma virus (HPV) with transitional cell carcinoma (TCC) of the urinary bladder in Israeli Jewish patients was assessed. One hundred and ten histopathological TCC sections were examined by peroxidase anti-peroxidase (PAP) method. HPV capsid antigen was demonstrated in 19 out of 110 cases (17.3%). HPV-DNA sequences, determined by in situ DNA-DNA hybridization at high stringency wash were present in 24 cases (21.8%): 16(14.5%) cases proved to be HPV6/11 and 8 (7.3%) were HPV 16/18 positive. Four (3.6%) of the HPV 6/11 positive specimens cross hybridized with HPV 31/33/35 at low stringency conditions. Sixteen samples known to be positive by in situ hybridization were reconfirmed by polymerase chain reaction (PCR). When the PCR was performed on the 43 negative cases, an additional 4(9.3%) HPV positive cases were revealed: two proved to be HPV 6/11 and two HPV 16/18. Comparison of the different methods for HPV detection in 59 TCC histopathological samples, showed good correlation; an overall positivity of 33.9% by PCR, 27.1% by in situ hybridization and 25.4% by PAP was observed. Forty one samples from nontumoral material of the bladder or post mortem specimens served as controls and 4.8% HPV DNA was present in only two cases: one HPV 6/11 and one 16/18. Hence, HPV in TCC of the bladder is detected at a relatively high frequency and might be involved in the pathogenesis of this tumor among Jewish population in Israel.

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The incidence in Israel of genital infection with herpes simplex virus (HSV) has been increasing steadily over the last two decades. During the years 1973-91, 1,508 patients had an HSV infection confirmed by viral culturing. The yearly incidence of new cases rose from sporadic cases in the seventies to 32.4 cases per 1,000 patients in 1990. The age distribution pattern did not change since 1980 and showed a peak incidence in subjects aged 20-40 years. The increase of HSV type 2 (HSV-2) infection rate in the Israeli population, as judged from specific geometric mean titers (GMT), rose from 15.25 in 1970 to 89.3 in 1991, while the GMT for HSV type 1 (HSV-1) did not increase significantly. The incidence of HSV-2 positive subjects (HSV-2/HSV-1 antibody ratio > or = 1) was low in the Jewish Israeli population, compared to other demographic areas. The predominant type of genital infection was HSV-2, although 21% of genital isolates were HSV-1.

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Patients on chronic dialysis who are supposed to disclose an impairment of the immune potential, seldom show clinical viral illnesses. Since severe varicella-zoster virus (VZV) infection develops in immunocompromised patients, we have examined the proliferative activity to VZV in the blood lymphocytes of 16 patients on continuous ambulatory peritoneal dialysis (CAPD) and compared it to healthy matched controls. The cellular in vitro response of these patients to specific VZV antigens was essentially normal. The mean stimulation index for CAPD patients was 7.06, and for matched controls 3.68 (p greater than 0.05). The mean percentage of lymphocytes in CAPD patients as determined by CD3 monoclonal antibodies was 57%, the CD4 helper and CD8 suppressor cells were 41 and 21%, respectively. When those 16 CAPD patients were followed up for the presence of anti-VZV IgA, IgM and IgG immunofluorescent antibody to membrane antigen antibodies during a period of 6 months, the recrudescence of VZV was documented by the appearance of IgA and IgM antibodies and/or fourfold increase in IgG titer in some patients, but no clinical illness was observed. The frequent reactivation of the virus without clinical symptoms in patients undergoing long-term intermittent chronic hemodialysis (HD) or CAPD was strengthened by the presence of increased anti-VZV geometric mean titers (52.68 and 53.00, respectively) in these patients as compared to control subjects (11.75).

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Laboratory confirmation of herpes simplex (HSV) infection in patients suspected of HSV encephalitis (HSV-E) at the earliest stage of the disease, may contribute greatly to the differential diagnosis and to the initiation of effective antiviral treatment. Our diagnosis of HSV infection was based on: a) detection of viral antigen in CSF cells in the first week of disease by immunofluorescence assay employing monoclonal antibodies against HSV-1 or HSV-2; b) detection of local IgM- and IgG-specific antibodies to HSV in the CSF and in the serum; c) ratio of titers of HSV antibodies in CSF and in serum less than 1:20; d) 4-fold rise in antibody titer to HSV in CSF and/or serum. The incidence of HSV-E was examined through 1987 in 270 patients suspected of viral infection of the central nervous system. In 187 (69.5%) material for laboratory diagnosis was inadequate and in 75 (27.8%) no evidence for infection by HSV was found. HSV infection was confirmed in 8 (2.9%), comprising 9.6% of those with adequate material for laboratory diagnosis. In no case was HSV isolated from the CSF. The importance of adequate material for viral diagnosis by the laboratory is emphasized.

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The availability of cloned varicella-zoster virus (VZV) DNA probes allows rapid detection of viral-specific DNA by "dot-blot" hybridization in lymphocytes or in lesion aspirates. Thirty-six blood specimens were obtained from 25 patients with suspected varicella or zoster. VZV-specific DNA was demonstrated in 15 lymphocyte preparations of nine patients with varicella and in one with disseminated zoster out of five patients with zoster. VZV-specific DNA was detected prior to rise in antibodies, indicating early viremia in these patients. Virus isolation from lesions and serological tests confirmed VZV infections. VZV-specific DNA was detected in lymphocytes of three patients out of six with active herpetic lesions, whereas it was not detected in lymphocyte specimens from two patients with undiagnosed rash or four with lymphoproliferative diseases, who did not present varicella or zoster, or from 18 healthy controls. No signal was obtained in herpes simplex virus (HSV)-infected and -uninfected cell lines. The hybridization assay proved that specific and viral or cellular DNAs other than VZV did not cross-hybridize with the probe. The sensitivity limit of detection was 4-15 pg of homologous DNA, and the assay was accomplished within 72-96 hr. These results point to the possible rapid diagnosis of VZV infection in patients suspected of varicella or generalized zoster. In addition, simultaneous infection with both VZV and HSV seems to occur in some patients.

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Sensitivity of herpes simplex virus (HSV) isolates, from patients with recurrent infections, to human fibroblast beta interferon (IFN), was tested in vitro. Among 25 HSV strains, 12 were HSV-1, isolated from facial and labial lesions, and 13 were HSV-2 isolated from genital lesions. Viral sensitivity to IFN was examined on epithelial MB cell line by yield reduction and plaque reduction and close correspondence between the two methods was observed. Most of HSV-1 isolates were in the same range of sensitivity to IFN, while HSV-2 isolates varied in sensitivity and differences approached statistical significance (P = 0.14). No correlation was found between various biological properties, such as plaque size, virulence in baby mice, growth at different temperatures, thymidine kinase activity in the presence or absence of IFN and sensitivity to IFN. Application of beta IFN containing cream reduced clinical symptoms in most of the patients. However, larger numbers of patients should be evaluated in order to conclude whether in vitro sensitivity correlates to clinical improvement.

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Antibody levels to Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV) and varicella-zoster virus (VZV) were determined in children with Hodgkin's disease (HD) before therapy, as well as in healthy, age-matched controls. Included were 21 Israeli-born children, aged 2.5 to 14.5 years: 13 Jews whose parents were of African-Asian origin, 1 Jew whose parents were of European origin, and 7 Arabs. Most of them were from large families (average 5.5 children per family) and low socioeconomic class. Antibody levels were not statistically different between patient and control groups with respect to CMV, HSV and VZV. Geometric mean titer of antibody to EBV viral capsid antigen in HD patients was 100.0 compared with 10.8 in controls. Thirty-three percent of controls were seronegative to EBV, and none had titers greater than or equal to 1:160. All patients but one were seropositive to EBV, and 8 of 20 had titers greater than or equal to 1:160. Among patients, 13 experienced onset of symptoms in the cold season (October to March) and 8 in the hot season (April to September). Onset during the cold season was usually abrupt with acute symptoms, Stage III to IV, involving the mediastinum and neck. Onset during the hot season was insidious, Stage I to II, with the affected area frequently located below the diaphragm. It is suggested that children of Arab and African-Asian Jewish origin with high serum titers to EBV are at increased risk for HD and for seasonal onset-associated clinical presentation.

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Antibody titers to Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex virus (HSV) Type 1, varicella-zoster virus (VZV) and rubella virus (RV) were determined in maternal and in newborn cord sera in 258 consecutive deliveries. Infants born with one or more of the following risk factors--weight less than 2.5 kg, Apgar score less than 7, clinical jaundice, meconium-stained amniotic fluid, birth defects and respiratory distress syndrome--were considered to be at risk. Similar geometric mean titers (GMT) of antibodies to EBV and HSV were seen in cord blood. Anti-VZV maternal antibody levels were significantly higher than those of cord blood (P less than 0.01). Levels of antibody to CMV and RV, the two viruses most implicated in fetal damage were significantly higher in cord blood than in maternal blood (P = 0.02, and P less than 0.001, respectively). Lower GMTs of antibodies to all five viruses were found in both maternal and cord sera of the group of infants at risk, as compared with infants without risk factors, while the ratio of maternal to cord blood antibody levels remained similar. It appears that inefficient production of antibodies correlates with the presence of risk factors in the newborn.

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Jewish women have been considered to be at low risk for genital herpes simplex virus Type 2 (HSV-2) infections. During the period 1973 to 1981, genital herpes simplex infections were laboratory confirmed in 129 cases (81 women and 48 men). Until 1976, only sporadic cases were reported to our laboratory. Since then, the number of cases has gradually increased, reaching 31 new reported cases in 1981. The age distribution was typical for a sexually transmitted disease, with the peak of infection at childbearing age (20 to 39 years). As a result, rising morbidity of neonates--due to active genital herpes virus infection in the mother during delivery--could be expected, and monitoring of high-risk pregnancies for prevention of perinatal infections was introduced. Of 14 pregnant women monitored, herpesvirus was isolated in 4 in the last week before delivery, and cesarean section was advised. In addition, during the last 3 years, neonatal herpes was confirmed in six, and suspected in three neonates whose mothers were not monitored for genital herpesvirus infection during pregnancy.

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Papillae were removed from a 2-yr-old boy with juvenile squamous cell papillomatosis and the tissue was grown in vitro. The method leading to the establishment of a continuous laryngeal papilloma cell line is described. This epithelial cell line was benign, as judged by cell morphology and cellular inability to form colonies in soft agar or to produce growing nodules in nude mice. Papilloma virus particles were not seen through the electron microscope. In the early stages of culture, the cells contained antigen that stained specifically with autologous serum.

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Viral antibodies were determined in paired maternal and cord blood sera of 258 consecutive deliveries. Antibodies to Epstein-Barr virus (EBV), cytomegalovirus (CMV), herpes simplex type 1 (HSV-1), adenovirus (ADV), and varicella zoster (VZV) were tested by indirect immunofluorescence and to rubella (RUB) by hemagglutination inhibition. Analysis of the overall pattern of differences between maternal and cord blood showed a highly significant difference for all six viruses. Analysis regarding individual viruses showed significantly higher titers to CMV and RUB in cord blood, a higher titer to VZV in maternal blood, and similar levels of antibodies to EBV, HSV-1, and ADV in maternal and cord blood. Infants with one or more risk indicators (weight less than 3 kg, Apgar score less than or equal to 7, clinical jaundice, meconium-stained amniotic fluid, respiratory distress syndrome) were defined as "at risk." Infants free of such indicators were defined as "normal." Significantly lower antibody levels to all six viruses were found in both maternal and cord blood of the "at risk" as compared to the "normal" group, while the ratios between the maternal and cord blood levels remained similar. Birth defects were found to have no effect on antibody titers. These results indicate an efficient and selective transfer through the placenta of certain viral antibodies and the possible association of lower antibody production with the presence of risk indicators in the infants.

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Ninety-eight cases of genital herpes simplex virus infection (HSV-2) were confirmed by laboratory examinations during the years 1973-80. Until 1975 there were less than five cases per year, but from 1976 the number of cases gradually increased, reaching 24 in 1980. The age distribution is typical of a sexually transmitted disease; and since the peak of susceptibility is at childbearing age, an increase in neonatal HSV infection could be expected. In 1980, laboratory testing confirmed neonatal HSV infection in four newborns. The need to monitor pregnancies in women at high risk for HSV-2 infection is stressed.

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Sera from 16 Jewish patients with histologically confirmed adenocarcinoma of the uterine cervix (AUC) and 32 control subjects matched by age and ethnic origin were examined for herpesvirus type 1 (HSV-1) and type 2 (HSV-2) neutralizing antibodies. Titers were determined by means of the quantitative plaque reduction neutralization test on VERO cell monolayers, using HSV-1 strain VR3 and HSV-2 strain. Significantly increased levels of antibodies against both virus strains were found in the AUC patients as compared with the controls. The trends in the AUC series resembled those in a previous similar case-control study of squamous cell carcinoma of the uterine cervix (SUC). Thus, the previously observed association between HSV-2 and SUC is true for AUC as well, despite differences in the clinical and epidemiologic characteristics of the two malignancies.

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A sensitive enzyme-linked immunosorbent assay (ELISA) is described for detection of varicella-zoster virus (VZV) IgM antibodies. The antigen consisted of a sonically disrupted extract of VZV-infected human embryo cells. The tested sera were absorbed with Staphylococcus aureus (strain Cowan I) before analysis. Rabbit anti-human IgM peroxidase conjugate was used to detect human IgM bound to viral antigen. The results were compared with those obtained by the indirect fluorescent antibody to membrane antigen (IFAMA) technique. Comparison of titers obtained by ELISA with those obtained by IFAMA for sera of chickenpox patients showed agreement between the results in 8 of 9 patients. In 1 chickenpox patient, no VZV IgM antibodies could be detected by IFAMA, while a titer of 3,200 was obtained by ELISA. The ELISA technique described gave titers more than 100 times higher than those obtained by IFAMA. VZV IgM antibody was detected by ELISA and IFAMA in only 1 of 5 zoster patients. No VZV IgM antibodies were found by ELISA in 45 control sera (healthy adults and hospitalized patients with various other diseases). Neither were they found in paired sera of 6 patients with acute herpes simplex infections, 2 patients with Epstein-Barr virus infections, and 3 patients with human cytomegalovirus infections.

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A technique using indirect immunoperoxidase antibody to membrane antigen (IPAMA) was developed for detection of IgG antibody to varicella-zoster virus (VZV). The IPAMA technique utilizes glass slides with air-dried VZV-infected cells, which can be stored at -70 C and used for several months without loss of sensitivity. Antibody titers measured by the IPAMA technique were comparable to those measured by the technique using indirect fluorescent antibody to membrane antigen (IFAMA) for sera obtained from 63 medical students as well as sera from three patients with chicken pox and nine with herpes-zoster infection, and the sensitivity of the IPAMA was equal to that of the IFAMA technique. No cross-reactivity with antibodies to other herpesviruses was observed.

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Infection of Raji cells by varicella-zoster virus (VZV) resulted in permissive infection with establishment of a persistently infected lymphoblastoid cell line. VZV antigens of the membrane and nuclear type, as detected by the indirect immunofluorescence membrane antigen (IFAMA) and anticomplement immunofluorescence (ACIF) tests, were observed. Minute amounts of infectious virus were detected by co-cultivation of VZV-infected Raji cells (Raji-VZV), with permissive human embryo fibroblasts (HEF). The virus isolated was found to be similar to the parent strain. Transient induction of Epstein-Barr viral capsid antigen (EB-VCA) was also observed. The persistently infected Raji-VZV cell line, when free of EB-VCA, was found suitable for measuring antibodies to varicella-zoster virus. The possible interaction in the infected Raji cells between EBV, which is implicated in human malignancy, and VZV which belongs also to the herpes group of viruses, is discussed.

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