Biomedical subjects
Publications and source records attributed to B Norrild.
Thirty-one patients with koilocytosis and/or concomitant CIN I were analysed for the presence of HPV types 11, 16 and 18 by in situ hybridization and Southern blot analysis. The prevalence of HPV was 48% and 55%, respectively, when measured by the two methods and among the HPV positive, HPV 11 and 16 were present in 47% and 60%, respectively, whereas HPV 18 was not found.
In a randomized study, we have evaluated the treatment of cervical human papillomavirus (HPV) lesions by CO2 laser vaporization. Fifty patients with abnormal Papanicolaou smears and histological evidence of cervical HPV infection associated or not with cervical intraepithelial neoplasia (CIN) grade I were randomized to either a treatment or a control group. The cervical swabs were obtained every 3 months in both groups and examined for HPV type 16 DNA by the polymerase chain reaction. After a follow-up period of 12 months no significant differences were found between the laser treatment and the control groups in relation to the disappearance of the abnormal Papanicolaou smear. Two patients in the treatment group and 3 in the control group had a conization because of development of CIN I or aggravation of the concomitant CIN found at the initial visit. The percentage of women who demonstrated HPV in their cervical smears at 12 months' follow-up was identical in the two groups, supporting the hypothesis that HPV is a persistent infection during which the virus is widespread in the vaginal epithelium.
Cervical swabs obtained from 164 women with histologically proven preinvasive and invasive cervical neoplasia were analysed for HPV type 11, 16 and 18 DNA by filter in situ hybridisation. HPV 16 or 18 was detected in 8 of 24 swabs from patients with invasive squamous cell carcinoma (33%), in 59 of 100 patients with carcinoma in situ or severe dysplasia (59%) and in 16 of 40 patients with mild or moderate dysplasia (40%). HPV 6 or 11 was found in only 2% of all swabs. Thirty-eight of the patients participated in a prospective follow-up study and were monitored non-invasively by cytology and colposcopy for 8 to 36 months. 25 patients had persisting or progressive lesions, 13 of which harboured HPV 16 or 18. Of 13 patients who had complete resolution of the dysplasia, only 2 were HPV-positive. The study indicates a significantly higher risk of malignant progression when the cervical dysplasia is associated with HPV 16 or 18 infection.
Vulvar intraepithelial neoplasia (VIN) is becoming more widespread and the patients are becoming still younger. Although progression to invasive vulvar carcinoma is uncommon, local recurrences are frequent and about one-quarter of the patients have multicentric genital disease. The aim of the present study was to search for a possible significant association of human papillomavirus (HPV) infection with vulvar carcinoma, recurrences, and multicentric disease. We used the polymerase chain reaction to examine vulvar and cervical biopsies from 43 patients with vulvar neoplasia for HPV type 16, which is the subtype most often detected in genital malignant or premalignant lesions. HPV 16 DNA sequences were found in 14 of 24 (58%) vulvar squamous carcinomas and in 15 of 19 (79%) VIN lesions. Nine patients (21%) had associated cervical neoplasia and six of these harbored HPV 16 in both lesions. Patients with recurrent intraepithelial neoplasia had a significantly higher incidence of HPV 16-positive lesions. No association was found with regard to the occurrence of multicentric disease or risk of malignant progression.
In a study carried out to estimate the prevalence of genital Human Papilloma Virus (HPV) infection among cervical cancer patients in Norway, the following values were recorded using the southern blot hybridization method: 54.1% HPV 16, 9.5% HPV 18, 0% HPV 11, and 1.4% HPV 16 and 18 coinfection, yielding a total of 62.2% HPV positive cases in the study. An attempt to include a normal biopsy as "internal control" from each patient failed, as macroscopically normal tissue was often histologically abnormal. HPV infection did not relate to stage of disease, age, or 5-year survival, whereas the classic relationship between stage and survival was observed. A very high percentage of HPV positive cases occurred among older women, a fact which does not support the existence of a new HPV epidemic. The studied population is unique, as it represents 75 cases which comprise a representative sample of the 372 incidental cases of cervical cancer in Norway in 1983. To our knowledge this is the first study of its kind.
Simultaneous immunocytochemical triple staining of ultrathin cryosections of herpes simplex virus type 1-infected cells was carried out using monoclonal antibodies specific for glycoprotein C, glycoprotein D and alpha + beta tubulin. The viral glycoproteins were identified in the cytoplasm, in the Golgi sacs, on the plasma membrane and on the surface of intra- and extracellular virus particles, but not on the nuclear membrane. The glycoproteins identified in the cytoplasm outside the Golgi region were not always confined to the membranes of vesicles, but were often located in close proximity to the tubulin-labelled structures. The glycoproteins C and D were usually codistributed in the cytoplasm, and both accumulated in the Golgi sacs in the same membrane domains. As the glycoproteins occur in close proximity to the microtubular structures, we speculate that these might be directly involved in the intracellular transport of viral glycoproteins.
Twenty-seven uterine cervical biopsies with histological diagnoses ranging from normal through dysplasia to invasive carcinoma were analysed for cytokeratin pattern in two-dimensional gel electrophoresis. No direct correlation between histological diagnosis and cytokeratin pattern was observed.
The cytokeratin pattern and the presence of human papillomavirus (HPV) were analyzed in 53 uterine cervical biopsies. The biopsies were histologically characterized and the diagnosis ranged from normal through dysplasia to carcinoma. The cytokeratins were identified by their immunological reactivity with the monoclonal antibodies AE1 and AE3. The tissue was typed for the presence of HPV types 11, 16 and 18. We have previously shown that there was no correlation between the expression of cytokeratins No. 14, 15, 16 and 19 (K14, K15, K16 and K19) and the histological diagnosis of cervical biopsies. The present study shows that the cytokeratin pattern cannot be correlated to HPV infection of the cervical tissue either.
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The mechanism of intracellular maturation and sorting of herpes simplex virus type I glycoproteins is not known in details. To elucidate the intracellular sorting of viral glycoproteins and their possible interaction with the cytoskeleton, a method for simultaneous immunogold staining of three antigens in ultrathin cryosections is described. Each antigen is stained by an indirect technique using mouse monoclonal IgG as first layer, rabbit anti-mouse IgG as second and gold-conjugated goat anti-rabbit IgG as third layer antibody. After each staining cycle the sections are covered by methyl cellulose and exposed to paraformaldehyde vapour at 80 degrees C for 30 min. This destroys the free antigen combining sites of the second and the third layer IgG and abolish contaminating staining. Simultaneous triple-staining is documented with three mouse monoclonal antisera specific for 1) herpes simplex virus type 1 glycoprotein C, 2) glycoprotein D and 3) alpha- and beta-tubulin as primary antibodies. Labelling for virus glycoproteins was found in some Golgi vesicles and close to the cytoplasmic microtubules as well as on the cell surface and on intracytoplasmic and extracellular virus particles.
We report a case of an apparently healthy 27-year-old man with a fatal course of papillomatosis, originating in the distal part of the esophagus and spreading into the main and intermediate bronchus. Human papillomavirus type 11, usually associated with juvenile laryngeal papillomatosis and genital condyloma acuminatum, was detected in the papillomas. In spite of treatment with CO2-laser evaporation of the papillomas, and with systemic as well as topical interferon, VP-16 and bleomycin, the papillomatosis progressed relentlessly during almost 2 years, and finally caused the death of the patient. We have no explanation for the malignant course of wart virus infection in this young man.
We examined the specificity and levels of antibodies present in rabbit tears after induced infection of the rabbit cornea. Two strains of herpes simplex virus-1 (HSV) with different patterns of ocular disease were used: RE which produces stromal disease, and F which produces epithelial disease. We found that (i) IgG, IgA, and IgM antibodies were produced, (ii) the number of specific HSV antigens recognized by these antibodies was no significantly different, and (iii) postinfection (PI) timing and concentration of antibodies varied according to the disease pattern of the virus strain. The animals infected with strain F produced high levels of IgG antibodies early PI which remained constant, while IgA and IgM antibodies also increased early PI but declined after Day 16 PI. Animals infected with strain RE showed low levels of IgA and IgM antibodies which remained low. IgG antibodies increased early PI but declined at Day 16 PI. These differences in times of appearance and in amounts of antibodies in tears may be related to the clinical course of the disease. It has been shown that stromal disease has an immunopathologic basis. Inflammation, cellular infiltration of lymphocytes, and plasma cells are seen in the stroma of RE-infected animals, but these are not present in the stroma of F-infected animals. Infectious virus was not isolated from corneal explants taken from animals during the quiescent stage of the disease. The difference in pathogenicity cannot be explained in terms of specificity of tear antibodies. Even though the disease patterns were different, the number and types of HSV polypeptides recognized by both sets of tears was similar. Consequently, we believe that the immunopathology seen in the stromal disease may be due to the anatomical site of HSV antigens, rather than to differences in specificity of tear antibodies.
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The titers of IgG and IgA to Pneumocystis carinii in 36 AIDS patients did not differ significantly from those in 31 controls. Only 2/15 patients (13%) with P. carinii pneumonia (PCP) had titers of IgM antibodies greater than or equal to 5, which is significantly less frequent than in 32 controls (62%) and in 21 AIDS patients without PCP (43%). The risk of PCP was 5 times higher in patients without IgM antibodies to P. carinii than in patients who had these antibodies. A significantly higher percentage of those without PCP (57%) showed increasing titers of IgM antibodies to P. carinii in the second of paired samples taken about 6 months apart, compared with whose with PCP (9%; p = 0.05). All patients had high titers of antibodies to CMV and HSV and normal total concentrations of immunoglobulins. None of the patients responded in lymphocyte transformation to P. carinii, CMV, or HSV antigens. There is no obvious explanation to the selective lack of IgM antibodies to P. carinii in patients with PCP. Lack of IgM antibodies may be a marker for an immunodeficiency to P. carinii.
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Artificial mixtures of the glycoproteins B, C, D, and E of herpes simplex virus 1 and 2 (HSV-1 and HSV-2), purified individually from infected Vero cell lysates by immunoaffinity to monoclonal antibodies, were bound to an aluminum hydroxide gel and were used to immunize mice, guinea pigs, and owl monkeys (Aotus trivirgatus) once or twice (mice and guinea pigs) to as many as four times (owl monkeys). In all animals tested, low levels of neutralizing antibodies were detected only after two or more immunizations. Lymphocyte transformation tests in owl monkeys suggested low or borderline levels of cellular immunity. The survival of immunized mice after intracerebral challenge was inversely related to the challenge dose. Immunized guinea pigs challenged by intravaginal inoculation showed reduced morbidity at the site of inoculation and were protected from CNS disease. Both immunized and nonimmunized monkeys were highly susceptible and could not be differentiated with respect to morbidity or mortality when challenged with 1,000 pfu of HSV-2 by the intravaginal route.
Herpes simplex virus type 1 (HSV-1) infection of human fibroblast cells grown in culture induces reorganization of the cytoskeleton fibrillar structures. Normal transport and insertion of HSV glycoproteins into the plasma membrane of the cells depend on the integrity of the microtubules. The natural host cells for HSV are epithelial cells, and an epithelial cell line established from rat palate was used in the present study. The effect of virus on the structure of the intermediate filaments and especially on the keratin proteins was studied. Two-dimensional gel electrophoresis of total cell extracts identified in uninfected cells two major acidic keratin proteins with apparent molecular weights of 44,000 (44K) and 48K (pI 5.45 to 5.30, 5.50 to 5.35). A new keratin protein of 46K (pI 5.40 to 5.25) appeared in infected cells between 8 h and 12 h post-infection. Pulse-chase experiments identified the 46K protein as a processed form of the 48K keratin component, which was also cleaved in uninfected cells grown in the presence of cycloheximide. Partial proteolysis of the 46K and 48K keratins with Staphylococcus aureus V8 protease showed that the 48K and the 46K proteins differed in only one oligopeptide. The significance of the changed keratin composition of HSV-infected cells is discussed.
C57 mice aged 8-10 weeks in groups of 50 each received vaginal cotton pellets soaked in lysates of HEp-2 cells, either mock-infected or infected with herpes simplex virus I, herpes simplex virus 2, and highly attenuated recombinant viruses 5 times a week for 89 to 114 weeks. An untreated group was also included. The mock-infected and some of the infected cell lysates were exposed to ultraviolet light at a dose sufficient to inactivate virus. Smears of exfoliated vaginal cells collected once a month and histopathologic sections of genital organs removed at autopsy were coded and examined blind for the presence of abnormal cells indicative of malignant changes and cervical cancer, respectively. Sera collected before termination of the study were tested blind for the presence of antibody to infected cell lysates and to purified herpes simplex virus glycoprotein B. The results were as follows: Over 74% of 826 mice examined at autopsy contained tumors at non-genital sites. The tumors were randomly distributed among the various groups. Gross genital abnormalities were less common in untreated animals than in mice receiving vaginal implants. The fraction of mice which developed cervical cancer diagnosed by histopathologic examination was small (7.2%) and not significantly different among various groups. There was no correlation between the presence of abnormal exfoliated cells indicative of early invasive or invasive cancer lesions and the histopathologically proven diagnosis of micro-invasive or invasive cervical cancer. The incidence and levels of antibody were highest in animals exposed to live virus; some mice exposed to inactivated virus also developed weak or moderately high antibody levels. The presence of antibodies did not correlate with the presence of histopathologically proven cervical cancer. The results do not support the ability of herpes simplex viruses to cause genital neoplasia in mice.