Herpes simplex virus and human papillomavirus in a population-based case-control study of cervical intraepithelial neoplasia grade II-III.

In order to evaluate the association between seropositivity for herpes simplex virus (type 1 and type 2) and cervical intraepithelial neoplacia (CIN), we analysed data from a population-based case-control study of CIN grade II-III which included Norwegian women aged 20 to 44 years, 94 cases and 228 controls. Our objectives were to determine if HSV-1 and/or HSV-2 seropositivity were independent risk factors for CIN, taking human papillomavirus exposure into account, and to elucidate the combined effect of HPV positivity and seropositivity for HSV In logistic regression analyses, the association between HSV-2 or HSV-1 seropositivity and CIN II-III was not explained by HPV (adjusted OR 3.0; 95%, CI 1.3-7.2 and adjusted OR 3.3; 95% CI 1.3-8.4, respectively). In analyses restricted to HPV-16 DNA-positive individuals, seropositivity for HSV-2 increased the risk of CIN (OR 11.1; 95% CI 1.2-105.7), whereas HSV-1 seropositivity was not significantly associated with CIN. In women positive for other HPV types, only HSV-1 seropositivity was associated with CIN (OR 8.5; 95% CI 1.3-55.8). In analyses of the HPV-16-seropositive individuals, neither HSV-1 nor HSV-2 seropositivity was associated with CIN. Compared to the reference group of jointly unexposed subjects, the HPV-16 DNA-positive women who were anti-HSV-2 negative had an increased risk of CIN (OR 29; 95% CI 12-67), whereas the risk in women who were both HPV-16 DNA-positive and HSV-2 was OR=247 (95% CI 31-1996). The estimate of interaction was strong, but did not reach significance, and our findings may suggest that the combined effect of the two viruses is of aetiological importance in cervical carcinogenesis. Furthermore, the results indicate that HPV DNA positivity is not sufficient to explain the sexual behaviour-associated risk of cervical neoplasia and that further studies on the role of genital HSV (type 1 as well as type 2) and other STDs are warranted.

Correlation between polymerase chain reaction and cervical cytology for detection of human papillomavirus infection in women with and without dysplasia.

The aim of this study was to compare the ability of two methods, the polymerase chain reaction (PCR) and cervical cytology, to detect HPV infection. The study population included 222 randomly selected women without dysplasia (controls) and 91 women with histologically confirmed dysplasia (CIN II-III) (cases). In women without dysplasia, 8.6% had cytological signs of HPV infection, whereas 15.3% were HPV DNA positive by PCR. In women with dysplasia, 72.5% had cytological signs of HPV infection, whereas 90.1% were HPV PCR positive. The statistical agreement between the two diagnostic methods was low (controls: kappa = 0.26, cases: kappa = -0.03). In total, PCR failed to detect 17 of 85 women with cytological signs of HPV infection, whereas cervical cytology failed to detect 48 of 116 HPV PCR-positive women. In women with dysplasia, but not in women without dysplasia, the oncogenic HPV types were associated with cytological signs of HPV infection.

A population-based case-control study of human papillomavirus-type-16 seropositivity and incident high-grade dysplasia of the uterine cervix.

In order to study the association between seropositivity against human papillomavirus-type-16 capsids and CIN II-III in the general population in ages at which high-grade cervical dysplasia arises, 90 cases and 216 controls participating in a population-based case-control study of incident CIN II-III, were analyzed for the presence of HPV antibodies, HPV DNA and for the influence of behavioral factors. A significantly higher proportion of cases than controls were seropositive. Of HPV-16-DNA-positive cases and controls, 42 and 14% respectively were seropositive. A similar proportion of seropositivity was found among the 172 cytologically normal, HPV-DNA-negative controls. However, seropositivity was closely linked to the sexual history of the women. Logistic-regression analyses, adjusting for sexual behavior, smoking history and educational level, revealed that CIN II-III was associated with HPV-16 seropositivity and with HPV DNA. Controlling for the presence of HPV DNA indicated that antibodies were not independently associated with CIN. The low correlation between the presence of HPV antibodies and DNA, the finding that the association between seropositivity and CIN depended on the presence of HPV DNA, and the association of seropositivity with sexual history, may be explained by serology detecting both past and present persistent infections and presence of HPV DNA, reflecting mostly transient infections in controls and persistent infections in cases.

Intratypic genome variability of echovirus type 30 in part of the VP4/VP2 coding region.

The genetic relationship of 33 echovirus type 30 (E30) isolates associated with three different outbreaks of meningitis in Norway and one outbreak in USA was assessed using direct sequencing of amplicons derived from a region covering part of the capsid proteins VP4 and VP2. The E30 sequences were compared to each other, and to other enteroviruses. Less sequence variation was observed between the isolates from a single outbreak (2-3%) than between groups of isolates from different outbreaks (4-9%). All observed nucleotide substitutions were amino acid silent. Homology between enteroviruses obtained from GenEMBL and the nucleotide consensus sequence generated from the E30 isolates varied between 44.8% (coxsackievirus A24) and 72.6% (coxsackievirus A9). Comparing the E30 sequences in this part of the genome with other enteroviruses, E30 clearly belongs to the coxsackie B-like virus group.

Prevalence of human papillomavirus in cervical scrapes, as analyzed by PCR, in a population-based sample of women with and without cervical dysplasia.

HPV is suspected of being a major cause of cancer of the uterine cervix. To understand the risk of disease in the general population of women, it is important to estimate the prevalence of HPV infection in a random population-based sample of women without disease. In this study, a total of 231 randomly selected women without dysplasia (controls) were examined, and compared with 103 women with histologically confirmed CIN II-III (patients). The prevalence of HPV DNA in cervical scrapes was determined by general nested PCR, which was expected to detect any relevant HPV type commonly found in cervical samples. The nested positive samples were typed with type-specific PCR. In the general nested PCR, 15% of the controls were positive, compared to 91% of the patients. In the population-based sample, 2.2% had HPV types 6 and 11 and 10% had types 16, 18, 31, and 33. In both groups, HPV DNA was observed less frequently in women above than below the age of 30. The results are among the few population-based figures on the prevalence of HPV in women, and provide a baseline for understanding the risk of developing cancer of the uterine cervix, and determining the proportion of women to be included in intervention studies.

Human papillomavirus and cervical intraepithelial neoplasia grade II-III: a population-based case-control study.

The association between certain human papillomaviruses (HPV) and cervical intraepithelial neoplasia (CIN) is well documented, but there is uncertainty about the strength of association and the role of co-factors is unclear. This population-based case-control study in Norwegian women 20-44 years of age included 103 cases with histologically confirmed CIN II-III and 234 age-matched and randomly selected controls. Cytological specimens from the cervix were analyzed using the polymerase chain reaction (PCR). In all, 91% of the cases and 15% of the controls were HPV DNA positive, giving a crude odds ratio (OR) of 67.2 (95% confidence interval: 28.6-157.5). The association between HPV 16 and CIN II-III was even stronger (crude OR = 123.9; 46.7 - 328.5). In logistic regression analysis, additional to HPV, only a high number of sexual partners and a low educational level contributed independently to the risk. The adjusted OR for the association between HPV and CIN II-III was 72.8 (95% CI: 27.6-191.9). The association between HPV and CIN remains very strong even after adjustment for proposed confounding factors. The results therefore support the role of HPV as a causative agent in the development of CIN.

[Gene therapy. Methods and applications]. / Genterapi. Metoder og anvendelser.

Modern techniques in molecular biology and cell biology will probably make gene therapy, i.e. therapeutic transfer of genes to the patient's cells, available for treatment of many genetic diseases, cancer, cardiovascular diseases and infectious diseases. For genetic diseases the treatment will involve the transfer of a functional copy of the defect gene. The strategy for treatment of cancer may include the transfer of genes that induce the death of cancer cells via toxic molecules, and genes that enhance the immune response to tumour cells. After several years of preclinical studies, the National Institutes of Health in the USA has, up to February 1994, approved 56 protocols for clinical trials in human gene therapy. Most of the protocols include use of viruses to aid gene delivery. This paper briefly reviews the scientific basis for gene therapy, and discusses some clinical applications of somatic gene therapy in humans.

Restriction endonuclease analysis of adenovirus type 3 isolated in Norway from 1970 to 1991.

Forty-three strains of adenovirus type 3 isolated from patients in Norway between 1970 and 1991 were analyzed with four restriction endonucleases. Bg1 II was the most discriminative enzyme. Five genotypes were identified and one of these has not been described before (Ad3a12). During both the epidemics in this period, new genotypes were introduced into the population. The same genotypes were identified in Norway as have previously been found in the northern parts of Europe, America and the Soviet Union.

[Amantadine and rimantadine against influenza A]. / Amantadin og rimantadin mot influensa A.

Amantadine and the analogue rimantadine have an antiviral effect on influenza A virus and are approximately 60% effective in preventing illness. The drugs are administered orally, and peak plasma concentration is achieved at two hours after a single dose. Side effects occur in 5-20% of the cases, but generally mild and transient and seen mainly with doses of more than 200 mg a day. This paper describes the mechanism of action and the pharmacokinetics of the drugs, and refers to some important clinical trials. Amantadine has been used in Norway to treat Parkinson's disease since 1972. The licensing of the amantadine and rimantadine for use against influenza A in this country is also discussed.

Genital human papilloma virus infection in Oslo studied by dot blot DNA hybridization and the polymerase chain reaction.

Samples from patients with genital condyloma acuminata or with cervical condylomas and/or dysplasia and from women without cytological/clinical evidence of cervical affection were examined by dot blot DNA hybridization or the polymerase chain reaction (PCR). The PCR was much more sensitive than dot blot, more than doubling the human papilloma virus (HPV) findings. HPV DNA, mainly HPV 6/11, was detected in 18 of 19 biopsies of condyloma acuminata, whereas HPV 16 was most frequently detected in the 21 cervices (76%) with condyloma and/or dysplasia. HPV 16 was detected in eight of 103 cervical smears with no signs of infection. The prevalence of HPV 16 in cervical samples was somewhat higher than expected. This suggests that, in Oslo, HPV 16 is a common HPV type in women with cytologically normal cervices. HPV 18 was relatively rare and was detected only in combination with other HPVs.

Strain variation in parainfluenza virus type 4.

Variations in epitopes on structural proteins of four isolates of parainfluenza virus type 4 (PIV-4) and the Mr of polypeptides in these isolates were determined by radioimmune precipitation assay with monoclonal antibodies to parainfluenza virus type 4A (PIV-4A) and type 4B (PIV-4B). Three isolates antigenically resembled the prototype PIV-4A and the sizes of their structural proteins were 72K (HN protein), 61K (F0 protein), 61K (NP protein) and 40K (M protein). However, one virus isolate showed marked antigenic differences from both the 4A and 4B prototype viruses, particularly with regard to properties of the HN and F proteins. In addition, both the NP and F0 proteins of this isolate had a slightly increased Mr of 63K.

Norwalk virus in Norway: an outbreak of gastroenteritis studied by electron microscopy and radioimmunoassay.

An outbreak of acute gastroenteritis affected approximately half of 40 children staying at a holiday centre in Southern Norway. By direct electron microscopy Norwalk-like viruses were demonstrated in 4/8 available stool specimens. No other pathogens were detected. Antibody against these viruses was demonstrated by immune electron microscopy in all of 7 convalescent phase sera but in none of 11 acute phase sera collected. Radioimmunoassay examination showed a rise in titre of Norwalk virus antibody in 6 available paired sera. This outbreak of Norwalk virus gastroenteritis in Norway was thus documented by a combined use of direct and immune electron microscopy and radioimmunoassay.

[Hybridization in situ. A new technic for the demonstration of viruses and gene products in histologic and cytologic specimens]. / In situ hybridisering. Ny måte til å påvise virus og genprodukter i histologisk og cytologisk materiale.

The use of in situ hybridization for light-microscopic demonstration of specific DNA or RNA-sequences is illustrated with examples. This method is useful for demonstration of viruses and gene products (mRNA) in individual cells in tissue sections or in cells in suspension. In situ hybridization technology is particularly useful in diagnostic pathology as an adjunct to the conventional methods for infectious diseases. In addition, the method is a powerful tool for analysing the interaction between viral infection and the induction and maintenance of certain human neoplasms. We discuss various aspects of tissue handling, fixation, hybridization procedures and detection of the hybridization signal. We also stress the importance of close cooperation between laboratories in the field of gene technology.

Nebulised beclomethasone dipropionate in recurrent obstructive episodes after acute bronchiolitis.

Forty four children with recurrent obstructive episodes after acute bronchiolitis in infancy were treated with nebulised beclomethasone dipropionate or placebo for eight weeks in a randomised double-blind study. They were seen monthly for a year afterwards, and also if they had acute respiratory illnesses with or without bronchopulmonary obstruction. The two treatment groups were well matched. The children receiving active treatment had significantly fewer symptomatic respiratory illnesses and fewer episodes of bronchopulmonary obstruction during the follow up period. The children given placebo had significantly higher obstructive scores during the study period, and they were treated with inhaled beta 2 agonists and theophylline for longer periods of time during the follow up period. The results suggest that nebulised beclomethasone dipropionate may have prolonged effects on subsequent asthmatic symptoms after termination of treatment in children with recurrent obstructive episodes after acute bronchiolitis.

Blood donor selection can prevent cytomegalovirus infection after open heart surgery.

Thirty-four patients without IgG antibodies against cytomegalovirus (CMV) prior to open heart surgery were studied. The patients were randomized to receive blood either from unselected donors, or from donors without detectable CMV antibodies. Fresh whole blood was mainly used. Eleven patients received CMV seronegative blood only. All had an uneventful convalescence period and remained seronegative. Ten of the 23 patients who received blood from unselected donors had typical CMV disease with the onset of symptoms in the third or fourth postoperative week, and fever lasting for two to three weeks. They all had liver enzyme release and later seroconversion against CMV. Four patients were hospitalized during this period. The incidence of symptomatic CMV infection after open heart surgery was higher than usually reported among the CMV seronegative patients. Selection of blood donors who lack antibodies against CMV may be an adequate protective measure. Avoidance of fresh blood and reduced use of blood products are presumably also of importance.

Acute bronchiolitis in infancy. The relationship to later recurrent obstructive airways disease.

Fifty-one infants admitted to hospital because of acute bronchiolitis were followed until 2 years of age. Sixty per cent had three or more attacks of bronchopulmonary obstruction, and the remainder two or less attacks. The children with three or more attacks also had more respiratory infections. They had younger parents and their close relatives more often had respiratory atopic illness. The children with three or more attacks wheezed for a longer time after the bronchiolitis. No difference was found for breast-feeding, neonatal respiratory complications, crowded homes, parental smoking and other social factors. To detect children at risk of recurrent obstructive airways disease after bronchiolitis, a discriminant analysis was performed. The discriminant function classified 28 of the 31 children with recurrent obstructive episodes as belonging to the risk group, and 18 of the 20 children with two or less episodes to the non-risk group.

Neutralizing activity in human milk fractions against respiratory syncytial virus.

Neutralizing activity against respiratory syncytial virus (RSV) was measured in milk samples from 17 healthy women whose infants had an acute infection with respiratory syncytial virus (RSV) and from 27 women with healthy infants. All milk samples were obtained 2-8 months post partum. Neutralizing activity was detected in 36 samples. No major difference in neutralizing titers was observed between the two groups, and the titers were low. RSV-specific IgA was found in two samples, and RSV-specific IgG in one sample. RSV-specific IgM was not detected. In gel filtration studies, the neutralizing activity was eluted with an apparent molecular weight above 400,000. The neutralizing activity remained after removal of IgA by affinity chromatography. These findings suggest that both immunoglobulin and non-immunoglobulin components in human milk can neutralize RSV.