HPV type-specific risks of high-grade CIN during 4 years of follow-up: a population-based prospective study.

We followed a population-based cohort of 5696 women, 32-38 years of age, by registry linkage with cytology and pathology registries during a mean follow-up time of 4.1 years to assess the importance for CIN2+ development of type-specific HPV DNA positivity at baseline. HPV 16, 31 and 33 conveyed the highest risks and were responsible for 33.1, 18.3 and 7.7% of CIN2+ cases, respectively. Women infected with HPV 18, 35, 39, 45, 51, 52, 56, 58, 59 and 66 had significantly lower risks of CIN2+ than women infected with HPV 16. After adjustment for infection with other HPV types, HPV types 35, 45, 59 and 66 had no detectable association with CIN2+. In summary, the different HPV types found in cervical cancer show distinctly different CIN2+ risks, with high risks being restricted to HPV 16 and its close relatives HPV 31 and HPV 33.

The ubiquity and impressive genomic diversity of human skin papillomaviruses suggest a commensalic nature of these viruses.

Human papillomaviruses (HPV) are epitheliotropic viruses, with some types suggested to be associated with skin cancer. In this study, swab samples collected from five different sites on the skin of renal transplant recipients, dialysis patients, and age- and sex-matched healthy controls were analyzed for HPV DNA by a newly designed PCR test. Most individuals were found to have asymptomatic HPV infections; more specifically, 94% of the renal transplant patients, 82% of the dialysis patients, and 80% of the healthy controls were positive for HPV DNA. The multiplicity of the HPVs detected was astounding: 20 previously described and 30 putatively new types were identified by cloning and sequencing of 33 samples from 13 individuals. These results demonstrate that normal human skin harbors an array of papillomaviruses, most of them previously unknown.

Prerequisites for human papillomavirus vaccine trial: results of feasibility studies.

BACKGROUND AND AIMS: Oncogenic human papillomaviruses (HPVs) are the major cause of cervical cancer and associated cancers. First generation preventive vaccines against HPVs are entering clinical trials. Therefore, it is time to consider prerequisites of field trials in Finland. RESULTS: Incidence of cervical cancer is increasing in young women which is not unexpected since risk taking behavior among young women has also increased. In the developed countries up to 44% of cervical cancer cases are attributable to HPV16 infection alone. However, high risk HPV types other than HPV16 and HPV18 are emerging in the population based on HPV DNA pilot screening studies. Annual attack rates among young women less than 25 years of age is 2.3% for HPV16 infection, and 0.03% for CIN3 invasive cervic cancer. Thus, sample size estimates for HPV vaccine efficacy trial are approximately 1000 when the endpoint is HPV16 infection, and approximately 15000 when the endpoint is >/=CIN3 or worse assuming that the vaccine efficacy is 70%. Both HPV vaccine trial acceptability and compliance rates at routine visits of the general Finnish female population are going to be high based on a pilot study. CONCLUSION: Prerequisites for large scale field trials on HPV vaccination are fulfilled in Finland.

Mucosal human papillomavirus types in squamous cell carcinomas of the uterine cervix and subsequently on fingers.

Human papillomavirus (HPV), especially type 16, is causally involved in the pathogenesis of anogenital cancer. There is an increasing number of reports of HPV infections in squamous cell carcinoma (SCC) of the fingers. A search of the Swedish cancer register covering the period 1958-94 inclusive for women with a history of genital and upper extremity SCC revealed 63 cases. Archival material from both cervical and cutaneous lesions was traced and analysed for the presence of HPV DNA in 32 of these patients. A newly developed 'neighbour primer' polymerase chain reaction (PCR) for HPV 16 DNA, aimed at overcoming the obstacle of cross-linked target DNA, was shown to be superior to conventional general and type-specific HPV PCR tests. HPV DNA was significantly more frequently found in digital tumours than in tumours at other cutaneous sites of the upper extremities [67% (10 of 15) vs. 7% (three of 43); P < 0.001]. Among 13 patients with a history of both cervical and finger SCC, HPV 16 was found in cervical samples from seven patients. From five of these seven patients, HPV 16 was also present in the corresponding finger lesions. The results support the hypothesis of a possible transmission of patients' genital HPV infections to fingers.

Betablockers: old concept in a modern approach.

In summary, carvedilol lowers blood pressure effectively. There is a decrease in left ventricular mass. Carvedilol has a good metabolic profile and seems to improve insulin sensitivity. Through its effects on the endothelial function and its antioxidative properties carvedilol has positive effects on the atherosclerotic process. Carvedilol also decreases microalbuminuria. In several aspects carvedilol differs from the conventional beta-blocking drugs, and some of these effects are now being investigated in new studies.

Detection of human papilloma virus DNA in lymph nodes extirpated at radical surgery for cervical cancer is not predictive of recurrence.

In women with recurrent cervical cancer after radical surgery, lymph node metastasis is detectable histologically at the time of surgery in only about 50% of cases. The present study was designed to determine whether the detection of human papilloma virus (HPV) DNA in lymph nodes extirpated at operation, as an indication of micrometastasis, is predictive of recurrence. Using polymerase chain reaction (PCR), a total of 140 lymph nodes from 31 patients with HPV 16 DNA positive primary cervical tumours were tested for the presence of an HPV 16 LCR/E6 gene fragment. HPV 16 DNA was detected in extirpated lymph nodes in 75% (6/8) of patients with recurrence (and who died within 5 years after surgery) and in 70% (16/23) of recurrence-free patients. In only four of the patients with recurrence (three of whom had HPV 16 DNA positive lymph nodes) was metastasis detectable histologically at surgery. HPV DNA positive lymph nodes were found in 91% (10/11) of patients with histologically detectable metastasis at surgery and in 60% (12/20) of patients without metastasis. It is concluded that the presence of HPV DNA in extirpated lymph nodes at cervical cancer operation does not appear to be predictive of tumour recurrence.

DNA analysis indicates patient-specific human papillomavirus type 16 strains in Bowen's disease on fingers and in archival samples from genital dysplasia.

Human papillomavirus (HPV) type 16 is casually involved in the pathogenesis of anogenital cancer and has also been demonstrated in some patients with Bowen's disease (BD) on the fingers. From two women with HPV 16 in BD on the fingers, and in archival samples from genital dysplasia, collected as long as 26 years ago, the non-coding region of the virus was amplified by the polymerase chain reaction and sequenced. The HPV 16 DNA sequences found in the finger lesions and in the genital archival samples showed no diversities within single patients. Compared with an HPV 16R reference sequence, one patient showed a unique T nucleotide at position 78, whereas the other patient exhibited T and A nucleotides at positions 7193 and 7521, respectively. In one of the patients, the same strain of HPV 16 was found in a digital tumour 26 years after its clearance from the genital tract. DNA sequence analysis indicated patient-specific HPV 16 strains. Auto-inoculation from the genital tract was favoured as a plausible explanation of why HPV 16 caused BD on the fingers.

HPV 16 DNA and mRNA in cervical brush samples quantified by PCR and microwell hybridization.

To quantitate HPV 16 DNA and mRNA, biotinylated amplicons from PCR and reverse transcription PCR were captured on streptavidin-coated microtitre plates. The amount of amplicon was determined by colorimetric detection after hybridization with an alkaline phosphatase-labelled probe. Dynamic ranges of between 4 and 6 log10, sufficient to cover the amounts of viral DNA and mRNA prepared from cervical samples were achieved. The reproducibility of the colorimetric detection step was reflected in coefficients of variation (C.V.) below 8%, considerably better than that of chemiluminescence detection. In a series of 89 HPV 16 DNA positive cervical samples, as compared with a CIN I/normal diagnosis subgroup, the number of HPV 16 genome copies per assay was significantly greater in a CIN II subgroup (P = 0.014), and a high-grade neoplasia subgroup (P = 0.040), and the content of HPV 16 mRNA significantly greater in the high-grade neoplasia subgroup (P = 0.0021). The number of mRNA equivalents per copy of viral DNA was higher for E5 than for the other three mRNA species analyzed (P < 0.001), and the concentration of E6*I mRNA was higher than those of the E6 full-length (P < 0.001) and E6*II (P < 0.001) transcripts. Despite these differences, no correlation was found between histological/cytological diagnosis and the amount of viral mRNA relative to the viral load.

Phylogenetic analysis of hepatitis D viruses indicating a new genotype I subgroup among African isolates.

Genetic analysis was performed on 13 hepatitis D virus (HDV) isolates from Ethiopia, Somalia, Jordan, Kuwait, Bulgaria, Moldavia, and Sweden. The complete nucleotide sequence and genomic organization are described for the first time for two African HDV isolates. Phylogenetic analysis showed all the African isolates to be intrarelated and to form a novel group within HDV genotype I; the suggested designation for this group is IC. The genetic distance to previously described type I isolates was about 0.15. The HDV genotype I isolates (total of 22 examined) phylogenetically formed three clusters, each of them corresponding to certain geographic regions; the "western" group consisted of six HDV isolates from western Europe and the United States plus one from Kuwait; the "eastern" group consisted of two isolates from Moldavia and one each from Bulgaria, Nauru, mainland China, and Taiwan; and the "African-Middle East" group consisted of six HDV isolates from Ethiopia and one from Somalia, Jordan, and Lebanon.

Cervical mucus antibodies against human papillomavirus type 16, 18, and 33 capsids in relation to presence of viral DNA.

To investigate whether cervical mucus antibodies against human papillomavirus (HPV) capsids are associated with the detection of HPV DNA or HPV-related cytological diagnoses, 611 samples of cervical secretions from 359 women referred to a colposcopy clinic were tested by an enzyme-linked immunosorbent assay for the presence of immunoglobulin A (IgA) antibodies against HPV capsids of HPV type 16, 18, or 33 and for the presence of cervical HPV DNA by PCR. Among subjects with at least one cervical sample positive for HPV type 16 (HPV-16) DNA, 28.1% also had at least one HPV-16 IgA-positive cervical sample (odds ratio [OR] = 2.9; P = 0.0003). IgA to HPV-18 was also more common among HPV-18 DNA-positive subjects (OR = 3.1; P = 0.0325) and IgA to HPV-33 was more common among HPV-33 DNA-positive subjects (OR = 4.2; P = 0.0023). Cervical IgA antibodies to HPV-16 were also more common among patients with cervical intraepithelial neoplasia, particularly among patients with cervical intraepithelial neoplasia grade I (P < 0.0005). The data indicate that an HPV type-restricted IgA antibody response against HPV capsids is detectable in cervical mucus and is associated with a concomitant cervical HPV infection.

Introduction of a new hepatitis agent in retrospect: genetic studies of Swedish hepatitis D virus strains.

The supposedly first outbreak of hepatitis D virus (HDV) infection in Sweden occurred among intravenous drug addicts in the Malmö area in the mid-1970s. Stored sera from this outbreak were used for viral RNA extraction and analysis. By sequence comparisons, the HDV genomes from those Swedish patients fell into two separate clusters, within which the RNA sequences were closely related. These two HDV groups genetically resembled the French and US-1 isolates of genotype I, respectively, indicating that there had been at least two separate sources of HDV infection. The genetic alterations of the HDV RNA were investigated by sequence analysis of nine annually drawn serum samples from one patient and paired samples collected between 2 and more than 10 years apart from six patients with chronic HDV infection. Only mutational changes were observed, and no insertion or deletion appeared throughout the periods observed. It was found that the Swedish HDV isolates mutationally evolved at an average rate of 1.1 x 10(-3) substitutions per nucleotide per year over a long time course of chronic HDV infection, which is of the same magnitude as that of other RNA viruses.

Long-term renal preservation in essential hypertension. Angiotensin converting enzyme inhibition is superior to beta-blockade.

Antihypertensive treatment is known to slow down the decline in glomerular filtration rate (GFR) with time. Angiotensin converting enzyme (ACE) inhibition has been shown to be more effective in this regard than conventional antihypertensive therapy. In a recent prospective, randomized, double blind trial in 257 patients with essential hypertension, the loss of GFR, determined with 51Cr-EDTA clearance, was significantly less with an ACE inhibitor (cilazapril) than with a beta-adrenoceptor blocker (atenolol) during the first year of treatment. However, after 2 years, the two therapies were equally effective in this regard, thereby creating doubts about the long-term superiority of ACE inhibition in this regard. In order to elucidate whether the superior renal preservation with the ACE inhibitor was a transient effect, GFR was measured after 1 more year of treatment, i.e., after 36 months. At that time, the decline in GFR was significantly smaller in the ACE inhibitor group as compared to the beta-adrenoceptor blocker group (-3.0 [-5.5, -1.0; 95% CI] v -7.0 [-9.0, -4.5; 95% CI] mL/min x 1.73 m2; P = .026). This demonstrates that in the treatment of essential hypertension ACE inhibition preserves GFR significantly better than beta-adrenoceptor blockade during long-term therapy.

Human papillomavirus type 70 genome cloned from overlapping PCR products: complete nucleotide sequence and genomic organization.

The genome of human papillomavirus (HPV) type 70 (HPV 70), isolated from a cervical condyloma, was obtained by cloning overlapping PCR products. By automated DNA sequence analysis, the genome was found to consist of 7,905 bp with a G + C content of 40%. The genomic organization showed the characteristic features shared by other sequenced HPVs. Nucleotide sequence comparison with previously known HPV types demonstrated the closest homology with HPV 68 (82%), HPV 39 (82%), HPV 18 (70%), HPV 45 (70%), and HPV 59 (70%). Comparison with seven other partially sequenced HPV 70 isolates showed homologies of between 100 and 99.5%. Cloning of overlapping PCR products and automated DNA sequence analysis was found to be a feasible method of obtaining full-length sequences of HPVs.

Factors in implant integration failure after bone grafting: an osteometric and endocrinologic matched analysis.

In a retrospective analysis of 49 patients who received bone graft augmentation to the maxillary sinuses in conjunction with implant insertion, 11 patients had a significantly reduced success rate. The aim of the present study was to determine whether bone quality, as assessed by osteometry and selected haematologic and urinary tests, influences the integration of implants, and whether such data can be prognostically useful. Relative bone mass density (BMD%) differed significantly among these patients as compared to age- and sex-matched control patients receiving the same reconstructive treatment (P=0.01). Other parameters tested did not demonstrate any significant differences. In addition to local complications, general disorders, such as osteoporosis, must be considered in cases of excessive implant loss.

Hepatitis A vaccination by intracutaneous low dose administration: a less expensive alternative.

We investigated the immune response to three different intracutaneous (i.c.) doses of inactivated hepatitis A vaccine: 72, 144, and 216 ELISA units (EU). The response was measured using a quotient score derived from a commercial enzyme-linked immunosorbent assay (HAVAB Abbott) and translated to IU per liter using a World Health Organization standard serum for hepatitis A virus antibody. The results were compared with the results obtained after an intramuscular (i.m.) full dose, i.e. 1,440 EU, at 0 and 6-12 months. As estimated from antibody concentration, 3 lots of 144 EU i.c. with 100% or two lots of 216 EU i.c. with 98% seroconversion results in at least as good early protection as the standard immunization with one lot of 1,440 EU i.m., (79% with our method). Indeed, only two doses of 144 EU vaccine (90% seroconversion) seem to give results comparable to the standard procedure. After the booster dose the median antibody concentration is 1,290 IU/l for the 144 EU vaccine and 837 for the 216 EU one, compared with an antibody response of 990 IU/l for the standard 1,440 EU i.m. vaccination. In conclusion, three doses of 144 EU vaccine i.c. or, as an alternative, two doses of 216 EU at monthly intervals give good early protection (e.g. before travel). After the booster dose, which is given 6 months to 1 year later, the serological response is comparable to the standard procedure of two doses of the 1,440 EU vaccine given i.m. and with 100% seroconversion in all three programs.

Increasing heterogeneity of the 'a' determinant of HBsAg found in the presumed late phase of chronic hepatitis B virus infection.

To investigate if the concomitant presence of hepatitis B virus (HBV) DNA and antibodies to hepatitis B surface antigen (anti-HBs) is associated with mutations in the HBV envelope gene, selected sequences of the HBV genome in 54 patients with chronic liver disease, collected from the Wuhan district of China, were amplified by polymerase chain reaction (PCR) and the DNA sequences of the products were determined. The part of the S gene coding for the 'a' determinant of HBsAg was found to be prone to diversity. A total of 19 aberations occurring at 11 of the 69 nucleotide positions of this part of the genome were found in sera from 15 HBsAg-negative but anti-HBs-positive patients. One of 13 HBsAg/HBeAg-positive and 8 of 17 HBsAg/anti-HBe-positive samples also showed point mutations in this gene sequence. Most prevalent was a point mutation from adenine to guanine at nucleotide 530 resulting in a change from threonine to alanine at amino acid position 126. This study highlights that the long time course of chronic HBV infection could favour a selection of escape mutants. The occurrence of such HBV variants in patients with chronic liver disease are not detected by conventional HBV serology, and the patients can therefore easily by be misdiagnosed. If viral mutants like those described here can be transmitted to other patients, there will be difficulties in identifying these infections, and conventional HBV vaccination will presumably not be protective against them.

Can a test for E6/E7 transcripts of human papillomavirus type 16 serve as a diagnostic tool for the detection of micrometastasis in cervical cancer?

Tissue from 11 cases of cervical cancer positive for human papillomavirus (HPV) type 16 DNA and 69 pelvic lymph nodes from the same patients were examined for HPV 16 DNA and mRNA from the E6/E7 genes. Five of the tumors were squamous, 3 adeno- and 3 adenosquamous carcinoma. From the primary tumors and the extirpated lymph nodes DNA and RNA or mRNA was subjected to PCR and RT-PCR. Three transcription profiles (only E6*I, E6*I and E6*II or full-length E6-E7 plus both of the spliced transcripts) were found in all of the 11 HPV 16 DNA-positive primary tumors. From the total of 69 lymph nodes analyzed 28 were positive for mRNA. HPV 16 DNA was found in 7 additional samples. Cytokeratin was found in 19 of these lymph nodes, indicating epithelial origin of tumor cells. Only 1 patient had 2 metastases evidenced by histology. These were both positive for HPV DNA and mRNA. The finding of HPV DNA, mRNA and cytokeratin in lymph nodes of patients with cervical cancer should be an indication of lymphogenically driven micrometastases of the tumor. The HPV mRNA assay should offer higher specificity than the DNA test since mRNA can be found in live cells only, while HPV DNA also can originate from dead cell material sequestered in the lymph nodes.

ACE inhibition preserves renal function better than beta-blockade in the treatment of essential hypertension.

Antihypertensive treatment can slow down the decline in glomerular filtration rate (GFR) with time. In patients with diabetic nephropathy, angiotensin converting enzyme (ACE) inhibition has been shown to be more effective in this regard than conventional antihypertensive therapy. Whether this applies to the much larger population of patients with essential hypertension is not yet known. In the present study, the effects of two different antihypertensive therapies on the loss of GFR with time, determined with Cr51-EDTA clearance after 6, 12 and 24 months of treatment, were assessed in a prospective, randomised, double-blind trial in 257 patients with essential hypertension. All had normal renal function and none had diabetes mellitus or glucosuria. Proteinuria (dipstick positive or trace) was detected in 7 patients initially. The two therapeutic modalities were the ACE inhibitor cilazapril and the beta-adrenoceptor blocking agent atenolol. Both therapies were equally effective in lowering systolic blood pressure (e.g. from 168 mmHg to 152 mmHg with cilazapril and from 170 mmHg to 155 mmHg with atenolol after 6 months, p < 0.001 for both). However, atenolol was slightly but significantly more effective in lowering the diastolic blood pressure at 6, 12 and 24 months. The decline in GFR with time was significantly smaller with cilazapril than with atenolol. After 6 months the reduction in GFR was 1.0 vs. 4.0 ml/min x 1.73 m2, p = 0.008 (cilazapril vs. atenolol) and after 12 months the corresponding changes were 2.0 vs. 4.5 ml/min x 1.73 m2, p = 0.04 and after 24 months 3.0 vs. 4.0 ml/min x 1.73 m2, respectively (n.s.).(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatitis C virus infection and chronic liver disease in Ethiopia where hepatitis B infection is hyperendemic.

To assess the prevalence and possible aetiological association of hepatitis C virus (HCV) with chronic liver disease and hepatocellular carcinoma (HCC), antibodies to HCV (anti-HCV) were determined by enzyme-linked immunosorbent and recombinant immunoblot assays in 500 healthy volunteer blood donors, 14 patients with chronic hepatitis, 156 cirrhotics and 68 cases of hepatocellular carcinoma (HCC) in Ethiopia. The prevalences of anti-HCV were 1.4%, 21%, 36% and 46%, respectively. There was no apparent risk factor to suggest the mode of transmission of HCV. Of the 238 patients, 65 (27%) had circulating hepatitis B surface antigen (HBsAg) (denoting current infection), 131 (55%) had antibodies to hepatitis B surface (anti-HBs) and/or core (anti-HBc) antigens (past infection) and 42 (18%) had no hepatitis B virus (HBV) marker. Anti-HCV antibodies were present in only one patient with HBsAg, in 54% with past infection and in 68% of those without HBV markers. Thus, HCV infection was uncommon in HBsAg-positive patients but significantly more common in patients with chronic liver disease and HCC who had evidence of past HBV infection or no marker for HBV infection. HCV infection appeared to be a more common cause of chronic liver disease and HCC than HBV infection in this population. However, considering the high prevalence of overall exposure to HBV infection (68% in healthy blood donors and 82% in those with chronic liver disease, including HCC), HBV is significant in terms of national preventive strategies.