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CCR5, a leukocyte chemoattractant receptor for chemokines CCL3, CCL4, and CCL5, promotes innate and adaptive immune responses by mediating leukocyte trafficking within lymph nodes and to peripheral tissues and is also known as a co-receptor for HIV cell entry. Homozygous inheritance of a complete loss-of-function mutation in CCR5 (CCR5Δ32/CCR5Δ32) is associated with symptomatic neuroinflammatory disease in humans with West Nile and Tickborne Encephalitis flavivirus infections. This study sought to establish whether CCR5 deficiency could also be a determinant of clinical outcome after infection by poliovirus which results in central nervous system damage in only a small proportion of cases. We analyzed serum samples from seven patients and 79 controls, collected during the 1984-1985 polio outbreak in Finland, where CCR5Δ32 is relatively common in the general population. The results excluded CCR5 deficiency as the sole determinant of severe neurologic disease after poliovirus infection in this population., (© 2013 Wiley Periodicals, Inc.)

Background: Hand hygiene is considered as an important means of infection control. We explored whether guided hand hygiene together with transmission-limiting behaviour reduces infection episodes and lost days of work in a common work environment in an open cluster-randomized 3-arm intervention trial., Methods: A total of 21 clusters (683 persons) were randomized to implement hand hygiene with soap and water (257 persons), with alcohol-based hand rub (202 persons), or to serve as a control (224 persons). Participants in both intervention arms also received standardized instructions on how to limit the transmission of infections. The intervention period (16 months) included the emergence of the 2009 influenza pandemic and the subsequent national hand hygiene campaign influencing also the control arm., Results: In the total follow-up period there was a 6.7% reduction of infection episodes in the soap-and water arm (p = 0.04). Before the onset of the anti-pandemic campaign, a statistically significant (p = 0.002) difference in the mean occurrence of infection episodes was observed between the control (6.0 per year) and the soap-and-water arm (5.0 per year) but not between the control and the alcohol-rub arm (5.6 per year). Neither intervention had a decreasing effect on absence from work., Conclusions: We conclude that intensified hand hygiene using water and soap together with behavioural recommendations can reduce the occurrence of self-reported acute illnesses in common work environment. Surprisingly, the occurrence of reported sick leaves also increased in the soap-and water-arm., Trial Registration: ClinicalTrials.gov: NCT00981877, Source of Funding: The Finnish Work Environment Fund and the National Institute for Health and Welfare.

Background: Mucosal coinfections with respiratory viruses and Streptococcus pneumoniae are common, but the role of rhinovirus infections in the development of invasive pneumococcal disease (IPD) in children has not been studied., Methods: During 1995 and 2007, we analyzed the association of IPD in children less than 5 years of age with respiratory virus epidemics by combining data from the National Infectious Disease Register, 3 prospective epidemiologic studies, and the database of the Department of Virology, University of Turku, Finland., Results: The mean IPD rate in children younger than 5 years of age in Finland was 2.9 cases per week (95% confidence interval [CI], 2.5-3.3) during periods of high rhinovirus activity, and 1.4 (95% CI, 1.2-1.6) during periods of low rhinovirus activity (P < 0.001). The IPD rate correlated with the rhinovirus activity recorded at the Department of Virology (correlation coefficient, 0.23; P = 0.001) and in the epidemiologic studies (correlation coefficients, 0.28, 0.25, and 0.31). The IPD rate was moderately increased during periods of high respiratory syncytial virus activity (mean, 2.1 cases per week; 95% CI, 1.8-2.3) compared with periods of low respiratory syncytial virus activity (mean, 1.7; 95% CI, 1.6-1.9; P = 0.008). There were no differences in the IPD rate between the periods of high and low influenza activity., Conclusions: Rhinovirus circulation in the community had an association with IPD in children younger than 5 years of age. This study suggests that rhinovirus infection may be a contributor in the development of IPD in the population of young children.

Background: Acute infectious diseases are major causes of short periods of days off from work, day care and school. These diseases are mainly caused by viruses and hands have a key role in their transmission. Thus, hypothetically, they can be controlled with means of intensified hand hygiene. In this study we aim to elucidate the effect of acute infectious diseases on the work contribution in common office work and study the influence of improved hand hygiene on possible reduction of infectious disease episodes and days off from work due to acute infectious diseases., Design: The voluntary participants have been recruited from six companies in the Helsinki region. The designated 21 study clusters were identified as operationally distinct working units each containing at least 50 people. The clusters were matched and randomized based on results of a pre-trial contagion risk survey. Improved hand hygiene is being executed with guided hand-washing with soap and water in one intervention arm and with alcohol based hand rubbing disinfectant in the other. Participants in both arms have received guidance on how to avoid infections and how to implement contagion stopping habits. A control arm is acting as before regarding hand hygiene. Data collection for evaluation of the efficacy of the interventions is based on self-reporting through weekly electronic reports. The questionnaire is enquiring about possible respiratory or gastrointestinal symptoms during the preceding week, and requests a daily report of presence of symptoms and working capacity. Etiology of the symptoms is not searched for individually, but contribution of different viruses is evaluated by sentinel surveillance, where occupational health clinics located in the premises of the participating companies collect specimens from employees visiting the clinic. Common causative agents of the diseases are being searched for using real-time PCR techniques. The duration of the intervention will be 16 months. Primary endpoints of the study are the number of reported infection episodes in a cluster within a time frame of 100 reporting weeks and the number of reported sick leave episodes in a cluster within a time frame of 100 reporting weeks., Trial Registration: ClinicalTrials.gov Identifier: NCT00821509.

In Finland, surveillance of potential re-emergence of poliovirus transmission is mainly based on environmental surveillance, i.e. search for infectious poliovirus in sewage samples. Since December 2008, 21 genetically highly divergent, neurovirulent vaccine-derived polioviruses (VDPV) have been isolated from sewage in Tampere, Finland. While the source of the VDPV is unknown, characteristics of the viruses resemble those of strains isolated from immunodeficient, persistently infected persons. No cases of suspected poliomyelitis have been reported in Finland since 1985.

In 1984, a wild type 3 poliovirus (PV3/FIN84) spread all over Finland causing nine cases of paralytic poliomyelitis and one case of aseptic meningitis. The outbreak was ended in 1985 with an intensive vaccination campaign. By limited sequence comparison with previously isolated PV3 strains, closest relatives of PV3/FIN84 were found among strains circulating in the Mediterranean region. Now we wanted to reanalyse the relationships using approaches currently exploited in poliovirus surveillance. Cell lysates of 22 strains isolated during the outbreak and stored frozen were subjected to RT-PCR amplification in three genomic regions without prior subculture. Sequences of the entire VP1 coding region, 150 nucleotides in the VP1-2A junction, most of the 5' non-coding region, partial sequences of the 3D RNA polymerase coding region and partial 3' non-coding region were compared within the outbreak and with sequences available in data banks. In addition, complete nucleotide sequences were obtained for 2 strains isolated from two different cases of disease during the outbreak. The results confirmed the previously described wide intraepidemic variation of the strains, including amino acid substitutions in antigenic sites, as well as the likely Mediterranean region origin of the strains. Simplot and bootscanning analyses of the complete genomes indicated complicated evolutionary history of the non-capsid coding regions of the genome suggesting several recombinations with different HEV-C viruses in the past.

Human rhinoviruses (HRVs), which are the most frequent causative agents of acute upper respiratory tract infections, are abundant worldwide. We have identified HRV strains in environmental specimens collected in Finland, Latvia and Slovakia during the surveillance of polio- and other enteroviruses. These acid-sensitive HRV strains were isolated under conditions optimized for growth of most of the enteroviruses, i.e. in stationary human rhabdomyosarcoma cells incubated at 36 degrees C. Phylogenetic analysis of the sequences derived from the partial 5' non-coding region and the capsid region coding for proteins VP4/VP2 and VP1 showed that the HRV field strains clustered together with prototype strains of the HRV minor receptor group. Partial sequences of the 3D polymerase coding region generally followed this pattern, with the exception of a set of three HRV field strains that formed a subcluster not close to any of the established HRV-A types, suggesting that recombination may have occurred during evolution of these HRV strains. Phylogenetic analysis of the VP4/VP2 capsid protein coding region showed that the 'environmental' HRV field strains were practically identical to HRV strains recently sequenced by others in Australia, the United States and Japan. Analysis of amino acids corresponding to the intercellular adhesion molecule-1 receptor footprint in major receptor group HRVs and also in the low-density lipoprotein receptor footprint of minor receptor group HRVs showed conservation of the 'minor receptor group-like' amino acids, indicating that the field strains may have maintained their minor receptor group specificity.

A nationwide programme to eliminate indigenous measles, mumps, and rubella, mainly by vaccinating children twice, was launched in Finland in 1982. Strong scientific methods to examine the immunological, clinical, and epidemiological variables have accompanied the programme. Measles was eliminated in 1996, and mumps and rubella in 1997. Now, 25 years from the start of this programme, Finland is facing new challenges. Since elimination, eight, 32, and six cases of measles, mumps, and rubella, respectively, have been reported. Of those, seven cases were failures of mumps vaccinations and one case was a rubella vaccination failure. Although outbreaks have been averted, the risks are increasing because the unvaccinated population is growing, epidemics occur in nearby countries, breakthrough cases arise, and declining antibodies suggest waning immunity. The chances for natural boosters are now at a minimum, and individuals are increasingly protected solely by vaccination. To maintain the absence of these diseases, the adopted policy should continue, but the country should also be prepared for prompt supplementary vaccinations in the case of epidemic outbreaks.

Several enterovirus serotypes should be considered as potentially diabetogenic. The capacity of an enterovirus to kill or impair the functions of human beta-cells can vary among the strains within a given serotype as shown previously for echovirus 9 and 30 (E-30). The evolution of E-30 has also shown patterns correlating with the global increase of type 1 diabetes incidence. In the present study, antigenic properties of a set of E-30 isolates were investigated and the results correlated with the previously documented beta-cell destructive phenotype of the strains, or to genetic clustering of the strains. No simple correlation between the three properties was observed. A full-length infectious clone was constructed and sequenced from one of the isolates found to be most destructive to beta-cells (E-30/14916net87). Phylogenetic analyses demonstrated that this strain was closely related to the E-30 prototype strain at the capsid coding region while outside the capsid region prototype strains of several other human enterovirus B serotypes clustered more closely. This suggests that the relatively greater pathogenicity of the strain might be based on properties of the genome outside of the structural protein coding region. Neutralizing antibody assays on sera from 100 type 1 diabetic patients and 100 controls using three different E-30 strains did not reveal differences between the groups. This finding does not support a previous proposition of aberrant antibody responses to E-30 in diabetic patients. It is concluded that identification of the genetic counterparts of pathogenicity of E-30 strains requires further studies.

The genus Enterovirus (family Picornaviridae) contains five species with strains isolated from humans: Human enterovirus A (HEV-A), HEV-B, HEV-C, HEV-D and Poliovirus. In this study, a proposed new serotype of HEV-D was characterized. Four virus strains were isolated from sewage in Egypt and one strain from acute flaccid paralysis cases in the Democratic Republic of the Congo. The complete genome of one environmental isolate, the complete coding sequence of one clinical isolate and complete VP1 regions from the other isolates were sequenced. These isolates had 66.6-69.4% nucleotide similarity and 74.7-76.6% amino acid sequence similarity in the VP1 region with the closest enterovirus serotype, enterovirus 70 (EV70), suggesting that the isolates form a new enterovirus type, tentatively designated enterovirus 94 (EV94). Phylogenetic analyses including sequences of the 5' UTR, VP1 and 3D regions demonstrated that EV94 isolates formed a monophyletic group within the species HEV-D. No evidence of recombination was found between EV94 and the other HEV-D serotypes, EV68 and EV70. Further biological characterization showed that EV94 was acid stable and had a wide cell tropism in vitro. Attempts to prevent replication with protective antibodies to known enterovirus receptors (poliovirus receptor, vitronectin alphavbeta3 receptor and decay accelerating factor) were not successful. Seroprevalence studies in the Finnish population revealed a high prevalence of this virus over the past two decades.

Background: Increasing evidence links chronic infections, especially burden of several infections, with increased risk for cardiovascular diseases (CVD). We studied joint immune response against two major periodontal pathogens and herpes simplex virus (HSV) in relation to established risk factors of CVD., Methods: Serum antibody levels to HSV, Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis were determined by ELISA. The study included 1107 subjects, 734 from Finland and 373 from Russia., Results: Combined antibody response to periodontal pathogens was associated inversely (OR, 95% CI) with high-density lipoprotein (HDL) cholesterol concentration (beta = 0.35; 0.20, 0.60; P < 0.001) and directly with HSV antibody quartiles: compared with the first quartile, ORs (95% CI) for quartiles 2-4 were 1.43 (0.88-2.32), 1.74 (1.07-2.82), and 1.89 (1.18-3.02), respectively (P for trend <0.001), after adjusting for age, gender, area, education, smoking, BMI, alcohol, triglycerides, and number of teeth. In linear regression analysis, the 3-pathogen antibody score (comprising antibody levels against periodontal pathogens and HSV) was inversely associated with HDL cholesterol concentration (beta = -0.067/1 mmol/l; -0.235, -0.018; P < 0.05)., Conclusions: HSV infection may promote infection by periodontal pathogens. Furthermore, the infectious burden comprising HSV and periodontitis may increase the risk for CVD by clearly decreasing HDL cholesterol concentrations.

The JC virus (JCV) genotyping method was used to gain insights into the population history of the Saami and the Finns, both speaking Finno-Ugric languages and living in close geographic proximity. Urine samples from Saami and Finns, collected in northern and southern Finland, respectively, were used to amplify a 610-bp JCV-DNA region containing abundant type-specific mutations. Based on restriction site polymorphisms in the amplified fragments, we classified JCV isolates into one of the three superclusters of JCV, type A, B, or C. All 15 Saami isolates analyzed and 41 of 43 Finnish isolates analyzed were classified as type A, the European type, and two samples from Finns were classified as type B, the African/Asian type. We then amplified and sequenced a 583-bp JCV-DNA region from the type A isolates of Saami and Finns. According to type-determining nucleotides within the region, we classified type A isolates into EU-a1, -a2, or -b. Most type A isolates from Saami were classified as EU-a1, while type A isolates from Finns were distributed among EU-a1, EU-a2, and EU-b. This trend in the JCV-genotype distribution was statistically significant. On a phylogenetic tree based on complete sequences, most of the type A isolates from Saami were clustered in a single clade within EU-a1, while those from Finns were distributed throughout EU-a1, EU-a2, and EU-b. These findings are discussed in the context of the population history of the Saami and the Finns. This study provides new complete JCV DNA sequences derived from populations of anthropological interest., ((c) 2005 Wiley-Liss, Inc.)

Objective: An earlier Finnish cohort study suggested that childhood viral CNS infections are associated with a fivefold increased odds of developing schizophrenia in adulthood. The authors sought to replicate this finding., Method: From the archives of the Department of Virology of the National Public Health Institute in Finland, 320 individuals born between 1960 and 1976 who had suffered virologically confirmed CNS infections before their 15th birthdays were identified. Of the infections, 202 had been caused by enteroviruses. The sample was followed up in the 1969-2000 records of the National Hospital Discharge Register of Finland to identify all cases of schizophrenia that emerged., Results: The cumulative incidence of schizophrenia was 0.94% in the whole sample and 0.99% among individuals who had suffered enteroviral infections. These rates are comparable to that found in the general population., Conclusions: Childhood viral CNS infections were not associated with increased risk of schizophrenia.

Previous studies have suggested that enterovirus infections during pregnancy may increase the risk of type 1 diabetes in the offspring. Our aim was to evaluate the role of first trimester enterovirus infections in a larger cohort of pregnant women. Two series of pregnant women were analyzed as follows: 948 women (series 1) and 680 women (series 2) whose child developed clinical diabetes before the ages of 15 or 7 years, respectively. An equal number of control women with a nondiabetic child was selected. Acute enterovirus infections were diagnosed by measuring IgM class antibodies against coxsackievirus B5 (series 1) and a mixture of coxsackievirus B3, coxsackievirus A16, and echovirus 11 antigens (series 2). In series 2, all sera were also analyzed for IgG class antibodies against an enterovirus peptide antigen. In addition, 152 randomly selected case-control pairs and all IgM-positive mothers' sera were tested for enterovirus RNA (series 2). In series 1, 3.1% of case women had IgM antibodies against coxsackievirus B5 antigen compared with 4.1% of control women (NS). In series 2, 7.1% of case and 5.3% of control women had IgM against the mixture of enterovirus antigens (NS). IgG class enterovirus antibodies did not differ between the groups. Enterovirus RNA was found only in one case woman (0.3%) of the subgroup of samples and in 5.7% of 70 IgM-positive women. The results suggest that enterovirus infection during the first trimester of pregnancy is not associated with increased risk for type 1 diabetes in the child.

The prevalence of human rhino-, entero-, and coronaviruses was investigated by RT-PCR in nasopharyngeal aspirates from 107 children without concurrent respiratory symptoms. The children were admitted to the hospital for elective surgery. The parents filled a questionnaire about the occurrence of respiratory symptoms four weeks before and two weeks after the surgery. The rate of viral detection was 45% in children with related past or recent respiratory infection whereas 20% of the samples taken from children without any related past or recent respiratory infections were positive for picornavirus RNA, P = 0.008. Thirty-one (29%) of the nasopharyngeal aspirates were positive for viral RNA, 18% for rhinovirus, and 11% for enterovirus RNA. Coronavirus RNA was not found in any of the children. Fifty-five percent of the children with virus-positive samples had an infection-related diagnosis. In addition, 81% of the children with virus-positive samples had had previously respiratory symptoms or there were concurrent respiratory symptoms in other family members. Only four of the 31 virus-positive samples were from children without infection-related diagnosis or recent past (or immediate future) respiratory symptoms., (Copyright 2002 Wiley-Liss, Inc.)

In order to assess the feasibility of environmental poliovirus surveillance, known amounts of poliovirus type 1, strain Sabin, were flushed into the sewage network of Helsinki. Grab specimens collected at a remote downstream location and concentrated about a 100-fold revealed infectious poliovirus on four successive days in all three separate experiments. As for concentration, a simple two-phase separation method was found to be at least as useful as a several-fold more resource-demanding polyethylene glycol (PEG) precipitation method. Recovery of the introduced virus was remarkably high (more than 10%). Using the current system, it might be possible to detect poliovirus circulation in a population of 700,000 people by examining a single 400 ml sewage specimen, if 1 out of 10,000 inhabitants were excreting the virus. It is concluded that environmental surveillance is a sensitive approach to monitor silent poliovirus circulation in populations served by a sewage network.

Background: Viral upper respiratory infections (URIs) are considered major risk factors for acute otitis media (AOM) in young children. We studied the epidemiology and relative roles of different viruses in respiratory infections in a cohort of 329 Finnish children followed from 2 months to 2 years of age., Methods: A nasopharyngeal aspirate (NPA) was collected whenever the child had signs and/or symptoms of URI and tested for the presence of common respiratory virus antigens or infectivity/nucleic acid (only rhinoviruses). Possible repeated detections of a given virus during a 30-day period were considered to represent a single designated virus-specific episode. AOM and URI episodes were defined in a similar way., Results: At least one virus was detected in 837 (41.7%) of the 2005 NPA specimens examined. Rates of URI and virus-specific episodes showed expected seasonal variation with major peak occurrences coinciding with or preceding those of AOM. The proportions of rhinoviruses, respiratory syncytial (RS) virus, parainfluenza virus (PIV) type 3, influenza virus A and adenoviruses were 63.1, 14.7, 6.7, 6.7 and 6.2% of the total of 761 virus-specific episodes. Influenza virus B, PIV1 and PIV2 were each responsible for approximately 1% of the episodes. AOM was diagnosed in 870 URI cases (43.4%) and in 43.3% of cases associated with a virus-positive NPA. The latter figure was clearly higher (57.7%) for RS virus-positive specimens., Conclusions: The seasonal coincidence of URI and AOM demonstrated the obvious role of URI in the pathogenesis of AOM. The occurrence of rhinoviruses and RS virus in URI was strikingly more common than that of any other virus tested. Although rhinoviruses were definitely the most frequently found viruses in NPA specimens, the association of RS virus with concurrent AOM was relatively higher than that of any other virus.

Genetic diversity among 107 coxsackievirus B4 field isolates has been studied. These isolates included clinical and environmental isolates originating from Finland, the Netherlands and France, and also from several other countries, including the USA. Three genomic regions were used for phylogenetic analyses: the VP1/2A junction, the entire VP1 and the VP4/VP2 region. Alignment of the deduced amino acid sequence in the VP1/2A junction revealed extensive sequence variation at the previously proposed cleavage site. MS analysis of proteolytic fragments from VP1 revealed that the exact cleavage site is situated between amino acid residues Thr-849 and Gly-850. At least seven distinct genetic lineages, or genotypes, had been circulating in Europe during the period 1959-1998. Two genotypes were endemic in the Netherlands during most of the investigated period. Genetically closely related strains could be found in different countries, and different genotypes co-circulated at the same time in a given country. Clustering patterns were identical in the three genomic intervals. In the VP4/VP2 region, the intraserotypic variation approached interserotype variation. Sequence comparisons of the entire VP1 gene gave a reliable genetic identification of enterovirus serotype. It is suggested that, for genotype classification of previously serotyped coxsackievirus B4 isolates, comparison of VP1/2A sequences is sufficient, but for more detailed investigation of genetic relationships, and for 'genetic serotyping', the entire VP1 gene should be used. The VP4/VP2 region is less reliable for genetic serotyping and genotyping, although the primers are able to amplify many different serotypes.

WHO recommends that surveillance of patients with acute flaccid paralysis (AFP) be used to demonstrate the eradication of wild poliovirus. In this article we report the results of a study to assess the frequency of AFP patients referred to Finnish hospitals and whether virological diagnostic coverage could be improved by repeated reminders and active feedback. For this purpose, we sent monthly questionnaires to all neurological and paediatric neurological units in Finland, requesting retrospective reporting on investigated paralytic patients with defined clinically relevant diagnoses, rather than AFP. Reminder letters included a pre-paid return envelope. Virological investigations were offered cost free. Of the 492 reporting forms sent, 415 (84%) were returned, evenly covering both the population and the study period (July 1997 to June 1998). Of the 90 patients reported, 83 were evaluable. The apparent incidences of the diagnoses covered were 1.6 per 100,000 at any age, and 1.0 per 100,000 for under--15-year-olds. Guillain-Barré syndrome was the most common diagnosis (0.80 per 100,000). The two faecal specimens required were virologically investigated in nine out of the 10 patients under 15 years of age, but in only 46% of all patients. Four adenovirus strains, but no polioviruses or other enteroviruses, were isolated. We conclude that a satisfactory monthly reporting system was readily established and that a sufficient number of patients with diagnoses resembling AFP are being referred to Finnish hospitals. Active feedback did not increase the proportion of virologically investigated patients to an acceptable level in all age groups. It is clear that other approaches must be used to quantify the circulation of poliovirus in Finland.

Occupational asbestos exposure can be demonstrated in 80% of mesothelioma cases. A possible role of simian virus 40 (SV40) in the etiology of mesothelioma was raised because several studies reported the presence and expression of SV40-like DNA sequences in human mesotheliomas. It is also known that expression of SV40 large T antigen inhibits cellular Rb and p53. This suggests that SV40 might render infected cells more susceptible to asbestos carcinogenicity. The SV40-like sequences are suggested to have arisen from contaminated polio vaccines. Millions of people in the United States and most European countries were inoculated with SV40-contaminated polio vaccine in 1955-1963. However, in Finland, where polio vaccination started in 1957, no SV40-contaminated vaccine was used. We used a polymerase chain reaction-based method to test for the presence of SV40-like sequences in DNA extracted from the frozen tumor tissues of 49 Finnish mesothelioma patients, most of whom had been occupationally exposed to asbestos. All of the Finnish tumor tissues tested negative for SV40-like sequences. The results suggest that the SV40-like sequences detected in mesothelioma tissue in some previous studies may indeed originate from SV40-contaminated polio vaccines. It is a matter of speculation whether the absence of SV40 infection has contributed to the relatively low incidence of mesothelioma in Finland (1/10(5) in 1990-1995)., (Copyright 1999 Wiley-Liss, Inc.)

Objective: The authors' goal was to determine whether there is an association between prenatal exposure to poliovirus infection and later development of schizophrenia., Method: All Finnish patients born between 1951 and 1969 with discharge diagnoses of schizophrenia (N = 13,559) were identified from the Finnish Hospital Discharge Register. Information on the monthly number of cases of paralytic poliomyelitis was obtained for each province in Finland. The authors analyzed the incidence of births of individuals who later developed schizophrenia by using a Poisson regression model with year and place of birth, age, sex, season of birth, and smoothed incidence of poliomyelitis in different gestational periods as explanatory variables., Results: An association between the incidence of poliomyelitis and the incidence of births 5 months later of individuals who later developed schizophrenia was observed. Without controlling for seasonality, the effect was significant throughout the second trimester., Conclusions: Second-trimester exposure to poliovirus infection may increase the risk for the later development of schizophrenia.

The viral etiology of measles- or rubella-like illnesses after MMR (measles, mumps, and rubella) vaccination was studied prospectively in 993 acutely ill Finnish children with fever and rash in 1983-1995. Their sera were tested for adeno-, entero-, and parvovirus B19 antibodies. Sera of 300 children <4 years old were also tested for human herpesvirus 6 (HHV-6) antibodies. Measles and rubella had been excluded by previous antibody testing. Serologic diagnosis of adeno-, entero-, or parvovirus infection was based on EIA (IgM or IgG antibodies) and that of HHV-6 on indirect immunofluorescence. A viral etiology was verified in 368 cases, most commonly parvovirus (20%), followed by enterovirus (9%) and adenovirus (4%). Among young children, HHV-6 infection was found in 37 (12%). Thirty-eight children (4%) had double infections. This study confirms that measles- or rubella-like illnesses in MMR-vaccinated children are often caused by other viruses. Each suspected vaccine failure requires laboratory confirmation to maintain reliable surveillance and control and to establish the specific etiology of the disease.

In a prospective multicentre study described previously on prediabetic events in siblings of index cases with insulin-dependent diabetes mellitus, 31 children developed clinical diabetes during the observation period and 51 children seroconverted for islet cell antibodies or insulin autoantibodies. By using nonserotype specific EIA and RIA, it has shown recently that enterovirus infections in both groups were frequently associated with increases of islet cell antibody and/or insulin autoantibody titres. Serum specimens sequentially collected from 12 children during the prediabetic period were still available and were then tested for serotype-specific neutralizing antibodies. Plaque-neutralization assays were carried out for coxsackievirus A9, coxsackievirus B types 1 to 6, and echovirus types 1 and 11. An unequivocal monotypic increase in neutralizing antibodies was observed on seven occasions in six children, on one occasion with coxsackievirus A9, one with coxsackievirus B1, two with coxsackievirus B2, two with coxsackievirus B3, and one with coxsackievirus B5. In four patients, the infection was associated temporally with increases in the levels of islet cell antibodies, insulin autoantibodies and/or antibodies to glutamic acid decarboxylase, and in three other patients, it coincided with the clinical onset of insulin-dependent diabetes mellitus. These results suggest that the association of enterovirus infections with insulin-dependent diabetes mellitus is not restricted to serotype 4 of coxsackie B viruses suspected previously, but that several different serotypes might play a role in the pathogenesis of the disease.

A retrospective analysis of the incidence of Guillain-Barré syndrome (GBS) in Finland in 1981-1986 was carried out by careful examination of medical records identified from nationwide Hospital Discharge Register data based on a mean total population of 5 million people. Records from 247 patients fulfilled the accepted criteria of GBS corresponding to a mean annual incidence of 0.82 per 100,000 population. Monthly rates showed an increased incidence of GBS in March 1985, following by a few weeks the onset of the nationwide oral poliovirus vaccine campaign and partly overlapping it. Analysis of the time series in depth suggested, however, that a change point in the occurrence of GBS had already taken place before the oral poliovirus vaccine campaign. Widespread circulation of wild-type 3 poliovirus in the population immediately preceded the oral poliovirus vaccine campaign and the peak occurrence of GBS. These results demonstrate a temporal association between poliovirus infection, caused by either wild virus or live attenuated vaccine, and an episode of increased occurrence of GBS, but they cannot prove the suspected cause-effect relation between GBS and oral poliovirus vaccine administration.

One thousand one hundred and sixty-one non-polio enterovirus strains, isolated during regular screening of Finnish sewage specimens, were analysed for serotype distribution seasonally through 20 years, and the findings were compared with similar data based on 1681 clinical isolates. Coxsackievirus B4 (CBV-4), CBV-5, echovirus 11 (EV-11), EV-6, CBV-2 and CBV-3 were the most common serotypes in sewage, whilst CBV-5, EV-11, coxsackievirus A9, EV-22, CBV-3 and EV-30 were the most common clinical isolates. Reasons for the differences are not known but several explanations are possible. Seasonal variation of enterovirus occurrence in both sources showed an expected peak in the autumn with a trough in the spring. The occurrence of enteroviruses was closely correlated with monthly recordings of mean relative humidity. A further observation concerning the clinical specimens in Finland was the relative excess of some serotypes, such as echovirus 22 and coxsackievirus A9, and paucity of others, for instance, echoviruses 4 and 9, when compared to published data from other countries. This is consistent with the idea of geographically restricted circulation of enteroviruses.

Coxsackievirus B infections have been associated with clinical manifestation of insulin-dependent diabetes mellitus (IDDM) in several studies, but their initiating role in the slowly progressing beta-cell damage is not known. This is the first prospective study designed to assess the role of coxsackie B and other enterovirus infections in the induction and acceleration of this process. Three separate series were studied: 1) an intrauterine exposure series comprising 96 pregnant mothers whose children subsequently manifested IDDM and 96 control mothers whose children remained nondiabetic; 2) a cohort of 22 initially unaffected siblings of diabetic children who were followed until they developed clinical IDDM (mean observation time, 29 months) and 110 control siblings who remained nondiabetic; 3) a case-control series comprising 90 children with newly diagnosed IDDM and 90 control subjects. Enterovirus infections were identified on the basis of significant increases in serum IgG, IgM, or IgA class antibodies against a panel of enterovirus antigens (capture radioimmunoassay). Enterovirus antibodies were significantly elevated in pregnant mothers whose children subsequently manifested IDDM, particularly in cases in which IDDM appeared at a very young age, before the age of 3 years (P < 0.005). Serologically verified enterovirus infections were almost two times more frequent in siblings who developed clinical IDDM than in siblings who remained nondiabetic (mean, 1.0 vs. 0.6 infections/follow-up year; P < 0.001). This difference was seen both close to the diagnosis of IDDM and several years before diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: To determine whether the effect of live attenuated oral polio virus vaccine given to pregnant women increases pregnancy complications., Methods: A study of women who had been vaccinated against poliovirus during a national vaccination campaign and who had delivered by cesarean section in three obstetrical hospitals in southern Finland. One thousand seven hundred and forty-seven vaccinated women (in three study cohorts), and their 2293 nonvaccinated controls (in two reference cohorts) were analyzed. Subjects are out of 22,000 deliveries evaluated earlier., Results: Vaccinated sectioned women did not show an excess of pregnancy complications. The mean rate of cesarean sections was 18.4% in the study cohorts and 18.9% in the reference cohorts counted from the 22,000 deliveries., Conclusions: Oral live attenuated polio virus vaccine does not increase pregnancy complications and is considered a safe alternative for vaccinating pregnant women.

Prompted by a nascent epidemic of poliomyelitis in Finland, a mass vaccination program with live oral poliovirus vaccine (OPV) was implemented in February and March 1985. The final rate of coverage was approximately 94%. Pregnant women were included, and a cohort study was launched to evaluate any harmful effects of OPV on the developing embryo. All records of births to mothers who were pregnant during the period of vaccination and whose infants were delivered at the three major hospitals in the Helsinki area were reviewed. Within the study cohort, mothers were grouped into three categories according to their trimester of pregnancy during the program. In addition, two reference cohorts were evaluated; these cohorts consisted of infants delivered at the same hospitals during the second half of 1984 and of 1986, respectively. Each of the three categories in the study cohort included approximately 3,000 children, while each reference cohort included approximately 6,000 children. Data were analyzed on the rate of intrauterine growth and the prevalences of stillbirth, neonatal death, congenital malformation, premature birth, perinatal infection, and neurological aberration. No differences were documented among the study and reference cohorts or among the three categories within the study cohort. Thus, under the conditions described here, the inclusion of pregnant women in programs of mass vaccination with OPV appears to be safe.

To examine the possible association between maternal vaccination with oral polio-virus and congenital malformations of the child, use was made of a nationwide mass vaccination in Finland. During a restricted period in 1985, a vaccination with trivalent oral poliovirus was implemented with coverage of 94% of the population. The study population was chosen from three major hospitals in the Greater Helsinki Region in Finland which deliver over 95% of the children of their catchment area. One study and two reference cohorts were delineated; the former consisted of pregnancies that were in their first trimester during the vaccination period. The two reference cohorts included mothers from the same hospitals whose pregnancies were likewise in the first trimester during the corresponding time period in 1984 and 1986, i.e., 12 months before and after the study period. Each cohort consisted of approximately 3,000 mothers/children whose delivery and hospital records were manually perused by trained nurses. All the structural malformations reflecting an impaired organogenesis during the sensitive first trimester were monitored. A total of 209 (2.3%) such malformations were recorded and characterized. There were no differences between the study and reference cohorts (risk ratio = 0.7, 95% confidence interval 0.5-1.0). According to the authors' power estimate, an additional prevalence greater than 0.5% would have been detected. The authors conclude that administration of oral poliovirus vaccine during early pregnancy was not associated with an elevated risk of congenital malformations.

Wild poliovirus type 3 isolates collected during the Finnish outbreak (1984 to 1985) in different geographical locations were compared by partial RNA sequencing. The entire 5' non-coding end and a discontinuous part of the capsid coding region were sequenced from 15 isolates. Combining the present sequence data with previously published data and analysing these by the maximum parsimony method showed that the epidemic strains had diverged in cocirculating lineages. Genetic comparison of strains isolated from a single person often revealed a branched structure in the phylogenetic tree indicating high potential for diversification. The extent of variation generated under immunological pressure during an infection lasting for weeks in one person was high as compared with the observed geographical variation.

Strains of poliovirus type 3 isolated in Finland in 1984 and 1985 (P3/Fin/84) are known to differ considerably from the type 3 vaccine strains in both nucleotide sequence and antigenic properties. In the search for the origin of the outbreak we first tested 80 type 3 strains that had been isolated elsewhere in the world during the years 1953 to 1986. An oligonucleotide probe complementary to a highly variable 17 nucleotide interval in the 5' non-coding region of the genomic RNA of P3/Fin/84 reacted with five strains. Also it was revealed that two of the latter five strains were related to the P3/Fin/84 strains in two separate genomic regions compared after partial RNA sequencing. One of them was isolated in Switzerland in 1980 and the other in Turkey in 1981. The Swiss strain was from a patient who had recently returned from a journey to various Mediterranean countries. Consequently, 16 other strains isolated in the late 1970s and early 1980s in Europe or in the Mediterranean countries were studied in detail by partial genomic sequencing and with neutralizing monoclonal antibodies. Two separate regions of the genome were compared by sequencing and corresponding dendrograms were constructed. The Switzerland and Turkey strains were found to be the strains most closely related to the viruses of the 1984 Finland epidemic. These results indicate that type 3 poliovirus strains related to P3/Fin/84 had been circulating in Mediterranean countries since the late 1970s.

A panel of nine neutralizing monoclonal antibodies was used to analyse the antigenic properties of 188 plaque-purified type 3 poliovirus strains from 17 faecal specimens, derived from eight people during a 2 month observation period. Most poliovirus specimens consisted of a mixture of antigenically distinct variants and the composition of the mixture was found to change between sequential specimens in many individuals, indicating antigenic evolution. Thirty-five strains representing different antigenic patterns were selected for partial sequencing of genomic RNA. Mutations leading to amino acid substitutions, as well as silent mutations, were seen at and close to the known antigenic sites. The frequency of silent mutations was used to estimate the evolutionary potential of the virus. The largest difference in silent changes between strains isolated from one person was 0.8%, which corresponds to a minimum of about 60 mutations per genome within a period of 3 weeks. The observed incidence of silent mutations between isolates from different persons was usually between 0.8 and 2%. These figures agree with the previously reported overall mutation rates of poliovirus, determined by other methods.

An indirect immunofluorescence test for detection of serum antibodies specific for nephropathia epidemica (NE) has been developed with use of acetone-fixed cryostat sections of the lungs of bank voles (Clethrionomys glareolus) that had been trapped from the NE-endemic area in Finland as antigen. NE antigen was detected as distinct fluorescence in the cytoplasm of alveolar and macrophage-like cells. The 16 patients studied included typical cases from an endemic area, cases from a family outbreak, and cases in a laboratory staff which had had close contact with infected bank voles. Antibodies reacting with antigen in the lung sections developed in all of the patients but they were not found in the preimmune sera of the patients, in the sera of patients with other renal diseases, or in the sera of healthy individuals, with the exception of a member of the laboratory staff who had lived in the endemic area for 20 years. No specific IgM antibodies to NE could be detected. The rise in titer of antibodies to NE was characteristically prolonged, and elevated antibody levels persisted for many years.

Serum antibodies against human coronavirus OC43 in different age groups were measured by complement fixation (CF), haemagglutination inhibition (HI), radial diffusion haemolysis-in-gel (HIG), and solid-phase radioimmunoassay (RIA) methods. Antigen grown in suckling mouse brain was used in all tests. Results obtained by the CF and HIG tests, and the RIA, were in good agreement with regard to the presence or absence of antibodies. Similar results were also obtained with the HI test if nonspecific haemagglutination inhibitors were first removed by treatment with phospholipase C and only titers of 1:20 or greater were considered positive. Children 6--23 months of age (n = 45) were without measurable coronavirus antibodies in all four assays. A rapid increase in the prevalence of antibodies then occurred in subsequent age groups, and practically all persons 6 years of age or older were found to have OC43 antibodies as measured by the HIG test or the RIA. The mean antibody levels determined by these two methods continued to increase, however, up to the age group of 10--14 years. This increase in antibody levels after the initial antibody incidence plateau may be due to boosting effects caused by related coronavirus strains, since OC43 antigens are known to cross-react with antibodies induced by other human coronaviruses. Taken together, these data suggest that OC43 virus, or an antigenically related coronavirus strain, is very common in Finland.

A nationwide vaccination campaign with oral poliovirus vaccine was organized in Finland in 1985 to halt an outbreak of poliomyelitis. Immunocompromised persons and their household contacts were excluded from the oral poliovirus vaccine target group and given instead a dose of inactivated poliovirus vaccine. This gave us an opportunity to determine whether immunocompromised persons are protected from poliomyelitis during an outbreak and oral poliovirus campaign. Fourteen children, ages 3 to 17 years, with leukemia were given a booster dose of a novel high antigen content, trivalent inactivated poliovirus vaccine. All but two responded by an at least 4-fold increase in serum-neutralizing antibodies to at least one poliovirus serotype. These results indicate that children with acute lymphocytic leukemia in remission respond well to a booster dose of inactivated poliovirus vaccine. Antibody concentrations to the uncommon local epidemic strain of type 3 poliovirus remained, however, relatively low in most patients (median, 1:6) suggesting relatively impaired heterologous response to vaccination. Possible spread of live vaccine viruses to the inactivated poliovirus-vaccinated children and their close contacts was evaluated by examining weekly fecal specimens from 20 children and their 19 regular adult contacts for cytopathic viruses. No polioviruses were isolated from 224 specimens examined, indicating that this high risk population was well-protected from unintended exposure to live polioviruses.

Concomitant with a nationwide oral poliovirus vaccine (OPV) campaign in Finland in 1985, an unexpected rise in the number of patients hospitalized with the Guillain-Barré syndrome (GBS) occurred. An analysis based on hospital records covering a population of 1.17 million and 6 years revealed a significantly increased incidence of GBS coinciding with the OPV campaign. We carefully examined 10 cases with onset of GBS within 10 weeks after immunization. Only 4 patients could recall recent symptomatic infection, and we found no specific agent in these cases. Our study suggests that live-attenuated polioviruses may, like other infectious viruses, sometimes trigger the GBS.

Virus isolated from an outbreak of poliomyelitis in Finland has been examined serologically and at the molecular level. The causative agent was an antigenically unusual strain of type 3 poliovirus, which was unrelated to the strains used to manufacture either live or killed poliovaccines. It is likely that the antigenic properties of the virus played a part in establishing a limited outbreak of poliomyelitis in a vaccinated population.

During an epidemic of acute gastroenteritis in Helsinki, in March--May 1976, 18 out of 40 adult patients showed electron microscopic and/or serologic evidence for rotavirus infection. Rotavirus was most frequently seen in the fecal suspensions from 2 to 6 days after the onset of the symptoms but persisted in one patient for as long as 10 days. An increase in the complement-fixing (CF) serum antibody titers against the related Nebraska calf diarrhea virus (NCDV), or an initially high titer and subsequent significant decrease, was seen in all but one patient with rotavirus-positive feces, and in 6 additional patients. This suggests that using electron microscopy as the only diagnostic procedure a considerable number of rotavirus infections in adults remain undetected. Immune response against autologous or homologous rotavirus was also documented by immunoelectron microscopy. Complement-fixing antibody titers against NCDV decreased significantly from the convalescence values over a half-year observation period, but still remained clearly above the titers of a gastroenteritis-negative control population.

Finland has been free of poliomyelitis since 1964 following a high coverage regular immunization programme using the Salk-type trivalent inactivated poliovirus vaccine. In late 1984 an outbreak of poliomyelitis with widespread circulation of poliovirus type 3 throughout the country was found. A thorough surveillance revealed 9 sporadic cases with acute persisting paralysis, all shown to be caused by poliovirus type 3. The preceding 20-year period free from poliomyelitis contributed to some diagnostic problems.