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  • Karppanen, Jari (Helsingin yliopisto, 2008)
    Environmentally benign and economical methods for the preparation of industrially important hydroxy acids and diacids were developed. The carboxylic acids, used in polyesters, alkyd resins, and polyamides, were obtained by the oxidation of the corresponding alcohols with hydrogen peroxide or air catalyzed by sodium tungstate or supported noble metals. These oxidations were carried out using water as a solvent. The alcohols are also a useful alternative to the conventional reactants, hydroxyaldehydes and cycloalkanes. The oxidation of 2,2-disubstituted propane-1,3-diols with hydrogen peroxide catalyzed by sodium tungstate afforded 2,2-disubstituted 3-hydroxypropanoic acids and 1,1-disubstituted ethane-1,2-diols as products. A computational study of the Baeyer-Villiger rearrangement of the intermediate 2,2-disubstituted 3-hydroxypropanals gave in-depth data of the mechanism of the reaction. Linear primary diols having chain length of at least six carbons were easily oxidized with hydrogen peroxide to linear dicarboxylic acids catalyzed by sodium tungstate. The Pt/C catalyzed air oxidation of 2,2-disubstituted propane-1,3-diols and linear primary diols afforded the highest yield of the corresponding hydroxy acids, while the Pt, Bi/C catalyzed oxidation of the diols afforded the highest yield of the corresponding diacids. The mechanism of the promoted oxidation was best described by the ensemble effect, and by the formation of a complex of the hydroxy and the carboxy groups of the hydroxy acids with bismuth atoms. The Pt, Bi/C catalyzed air oxidation of 2-substituted 2-hydroxymethylpropane-1,3-diols gave 2-substituted malonic acids by the decarboxylation of the corresponding triacids. Activated carbon was the best support and bismuth the most efficient promoter in the air oxidation of 2,2-dialkylpropane-1,3-diols to diacids. In oxidations carried out in organic solvents barium sulfate could be a valuable alternative to activated carbon as a non-flammable support. In the Pt/C catalyzed air oxidation of 2,2-disubstituted propane-1,3-diols to 2,2-disubstituted 3-hydroxypropanoic acids the small size of the 2-substituents enhanced the rate of the oxidation. When the potential of platinum of the catalyst was not controlled, the highest yield of the diacids in the Pt, Bi/C catalyzed air oxidation of 2,2-dialkylpropane-1,3-diols was obtained in the regime of mass transfer. The most favorable pH of the reaction mixture of the promoted oxidation was 10. The reaction temperature of 40°C prevented the decarboxylation of the diacids.
  • Pastell, Helena (Helsingin yliopisto, 2010)
    Arabinoxylo-oligosaccharides (AXOS) can be prepared enzymatically from arabinoxylans (AX) and AXOS are known to possess prebiotic potential. Here the structural features of 10 cereal AX were examined. AX were hydrolysed by Shearzyme® to prepare AXOS, and their structures were fully analysed. The prebiotic potential of the purified AXOS was studied in the fermentation experiments with bifidobacteria and faecal microbiota. In AX extracted from flours and bran, high amounts of a-L-Araf units are attached to the b-D-Xylp main chain, whereas moderate or low degree of substitution was found from husks, cob and straw. Nuclear magnetic resonance (NMR) spectroscopy showed that flour and bran AX contain high amounts of a-L-Araf units bound to the O-3 of b-D-Xylp residues and doubly substituted b-D-Xylp units with a-L-Araf substituents at O-2 and O-3. Barley husk and corn cob AX contain high amounts of b-D-Xylp(1→2)-a-L-Araf(1→3) side chains, which can also be found in AX from oat spelts and rice husks, and in lesser amounts in wheat straw AX. Rye and wheat flour AX and oat spelt AX were hydrolysed by Shearzyme® (with Aspergillus aculeatus GH10 endo-1,4-b-D-xylanase as the main enzyme) for the production of AXOS on a milligram scale. The AXOS were purified and their structures fully analysed, using mass spectrometry (MS) and 1D and 2D NMR spectroscopy. Monosubstituted xylobiose and xylotriose with a-L-Araf attached to the O-3 or O-2 of the nonreducing end b-D-Xylp unit and disubstituted AXOS with two a-L-Araf units at the nonreducing end b-D-Xylp unit of xylobiose or xylotriose were produced. Xylobiose with b-D-Xylp(1→2)-a-L-Araf(1→3) side chain was also purified. These AXOS were used as standards in further identification and quantification of corresponding AXOS from the hydrolysates in high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) analysis. The prebiotic potential of AXOS was tested in in vitro fermentation experiments. Bifidobacterium adolescentis ATCC 15703 and B. longum ATCC 15707 utilized AXOS from the AX hydrolysates. Both species released L-arabinose from AXOS, but B. adolescentis consumed the XOS formed, whereas B. longum fermented the L-arabinose released. The third species tested, B. breve ATCC 15700, grew poorly on these substrates. When cultivated on pure AXOS, the bifidobacterial mixture utilized pure singly substituted AXOS almost completely, but no growth was detected with pure doubly substituted AXOS as substrates. However, doubly substituted AXOS were utilized from the mixture of xylose, XOS and AXOS. Faecal microbiota utilized both pure singly and doubly substituted AXOS. Thus, a mixture of singly and doubly substituted AXOS could function as a suitable, slowly fermenting prebiotic substance. This thesis contributes to the structural information on cereal AX and preparation of mono and doubly substituted AXOS from AX. Understanding the utilization strategies is fundamental in evaluating the prebiotic potential of AXOS. Further research is still required before AXOS can be used in applications for human consumption.
  • Larjavaara, Meri (Helsingin yliopisto, 2000)
  • Einola, Eeva (Helsingin yliopisto, 2013)
    This work is focused on how external factors influence fluxes of the key nutrients, nitrogen, phosphorus and carbon in boreal streams and rivers and thus control the annual and inter-annual dynamics in chemistry and biology of the recipient lakes. Approaches and research tools applied in the study include long-term monitoring, field measurements, budget calculations, comparative studies, statistical modeling and mechanistic process-based modeling. Study on the influence of climatic factors showed that precipitation and air temperature can explain a high proportion of the annual and seasonal variability in river nutrient concentrations. However, the relationships between the weather and water quality are often masked by time lags in hydrology, seasonality and complexity of all the affecting factors. To define the study to the influence of hydrology on nitrate (NO3) in rivers, NO3 concentrations and loads were compared between summer seasons with high and low discharge. The highest concentrations were observed during the high discharge summers when the summer NO3 load comprised more than half of the annual load. This caused remarkable changes on the nutrient levels in the recipient lake during high discharge summers, affecting the ecosystem of the lake during the growing season. The mass balance calculations for the recipient lake, Lake Pääjärvi, showed that the mean annual retention for total phosphorus (tot P) in the lake was as high as 74% while the values were lower for total nitrogen (tot N) (27%) and total organic carbon (TOC) (34%). It is evident that Pääjärvi has the effect of decreasing nutrient concentrations downstream. The results of the study of carbon (C) in a chain of five lakes highlighted the effect of the lake size and its setting on the catchment. Hydrological import and export of TOC dominated the carbon fluxes especially in the small drainage lakes in the middle of the chain. In-lake processes presumably had greater influence on the C fluxes in the large lakes in the study. On the landscape scale, small lakes (area less than 1 km2) were important in the net accumulation of C in the sediments, since they were responsible for 56% of the net C accumulation in all the lakes although they formed only 14% of the entire lake area. On the other hand, the large lowland lakes (size class 10 50 km2) played a more important role in the fluxes of CO2 to the atmosphere. In the future, the increasing frequency of heavy precipitation events and wet/dry periods may further strengthen the variability in timing and magnitude of nutrient loads, but there will be variation in the response of lakes and rivers. This will largely depend on the characteristics of the lakes and rivers as well as on the properties of their catchments.
  • Hovi, Petteri (Helsingin yliopisto, 2011)
    Background: The improved prognosis of early preterm birth has created a generation of surviving very low birth weight (< 1500 g, VLBW) infants whose health risks in adulthood are poorly known. Of every 1000 live-born infants in Finland, about 8 are born at VLBW. Variation in birth weight, even within the normal range, relates to considerable variation in the risk for several common adult disorders, including cardiovascular disease and osteoporosis. Small preterm infants frequently exhibit severe postnatal or prenatal growth retardation, or both. Much reason for concern thus exists, regarding adverse health effects in surviving small preterm infants later lives. We studied young adults, aiming at exploring whether VLBW birth and postnatal events after such a birth are associated with higher levels of risk factors for cardiovascular disease or osteoporosis. Subjects and Methods: A follow-up study for VLBW infants began in 1978; by the end of 1985, 335 VLBW survivors at Helsinki University Central Hospital participated in the follow-up. Their gestational ages ranged from 24 to 35 weeks, mean 29.2 and standard deviation 2.2 weeks. In 2004, we invited for a clinic visit 255 subjects, aged 18 to 27, who still lived in the greater Helsinki area. From the same birth hospitals, we also invited 314 term-born controls of similar age and sex. These two study groups underwent measurements of body size and composition, function of brachial arterial endothelium (flow-mediated dilatation, FMD) and carotid artery intima-media thickness (cIMT) by ultrasound. In addition, we measured plasma lipid concentrations, ambulatory blood pressure, fasting insulin, glucose tolerance and, by dual-energy x-ray densitometry, bone-mineral density. Results: 172 control and 166 VLBW participants underwent lipid measurements and a glucose tolerance test. VLBW adults fasting insulin (adjusted for body mass index) was 12.6% (95% confidence interval, 0.8 to 25.8) higher than that of the controls. The glucose and insulin concentrations 120 minutes after 75 g glucose ingestion showed similar differences (N=332) (I). VLBW adults had 3.9 mmHg (1.3 to 6.4) higher office systolic blood pressure, 3.5 mmHg (1.7 to 5.2) higher office diastolic blood pressure (I), and, when adjusted for body mass index and height, 3.1 mmHg (0.5 to 5.5) higher 24-hour mean systolic blood pressure (N=238) (II). VLBW birth was associated neither with HDL- or total cholesterol nor triglyceride concentrations (N=332) (I), nor was it associated with a low FMD or a high cIMT (N=160) (III). VLBW adults had 0.51-unit (0.28 to 0.75) lower lumbar spine Z scores and 0.56-unit (0.34 to 0.78) lower femoral neck Z scores (N=283). Adjustments for size attenuated the differences, but only partially (IV). Conclusions: These results imply that those born at VLBW, although mostly healthy as young adults, already bear several risk factors for chronic adult disease. The significantly higher fasting insulin level in adults with VLBW suggests increased insulin resistance. The higher blood pressure in young adults born at VLBW may indicate they later are at risk for hypertension, although their unaffected endothelial function may be evidence for some form of protection from cardiovascular disease. Lower bone mineral density around the age of peak bone mass may suggest increased risk for later osteoporotic fractures. Because cardiovascular disease and osteoporosis are frequent, and their prevention is relatively cheap and safe, one should focus on prevention now. When initiated early, preventive measures are likely to have sufficient time to be effective in preventing or postponing the onset of chronic disease.
  • Jakobsson, Maija (Helsingin yliopisto, 2009)
    Cervical cancer is the second most common cancer among women globally. Most, probably all cases, arise through a precursor, cervical intraepithelial neoplasia (CIN). Effective cytological screening programmes and surgical treatments of precancerous lesions have dramatically reduced its prevalence and related mortality. Although these treatments are effective, they may have adverse effects on future fertility and pregnancy outcomes. The aim of this study was to evaluate the effects of surgical treatment of the uterine cervix on pregnancy and fertility outcomes, with the focus particularly on preterm birth. The general preterm birth rates and risk factors during 1987–2005 were studied. Long-term mortality rates of the treated women were studied. In this study, information from The Medical Birth Register (MBR), The Hospital Discharge Register (HDR), The Cause-of-Death Register (CDR), and hospital records were used. Treatments were performed during 1987–2003 and subsequent deliveries, IVF treatments and deaths were analyzed. The general preterm birth rate in Finland was relatively stable, varying from 5.1% to 5.4% during the study period (1987 to 2005), although the proportion of extremely preterm births had decreased substantially by 12%.The main risk factor as regards preterm birth was multiplicity, followed by elective delivery (induction of delivery or elective cesarean section), primiparity, in vitro fertilization treatment, maternal smoking and advanced maternal age. The risk of preterm birth and low birth weight was increased after any cervical surgical treatment; after conization the risk of preterm birth was almost two-fold (RR 1.99, 95% CI 1.81– 2.20). In the conization group the risk was the highest for very preterm birth (28–31 gestational weeks) and it was also high for extremely preterm birth (less than 28 weeks). In this group the perinatal mortality was also increased. In subgroup analysis, laser ablation was not associated with preterm birth. When comparing deliveries before and after Loop conization, we found that the risk of preterm birth was increased 1.94-fold (95% CI 1.10–3.40). Adjusting for age, parity, or both did not affect our results. Large or repeat cones increased the risk of preterm birth when compared with smaller cones, suggesting that the size of the removed cone plays a role. This was corroborated by the finding that repeat treatment increased the risk as much as five-fold when compared with the background preterm birth rate. We found that the proportion of IVF deliveries (1.6% vs. 1.5%) was not increased after treatment for CIN when adjusted for year of delivery, maternal age, or parity. Those women who received both treatment for CIN and IVF treatment were older and more often primiparous, which explained the increased risk of preterm birth. We also found that mortality rates were 17% higher among women previously treated for CIN. This excess mortality was particularly seen as regards increased general disease mortality and alcohol poisoning (by 13%), suicide (by 67%) and injury death (by 31%). The risk of cervical cancer was high, as expected (SMR 7.69, 95% CI 4.23–11.15). Women treated for CIN and having a subsequent delivery had decreased general mortality rate (by -22%), and decreased disease mortality (by -37%). However, those with preterm birth had increased general mortality (SMR 2.51, 95% CI 1.24–3.78), as a result of cardiovascular diseases, alcohol-related causes, and injuries. In conclusion, the general preterm birth rate has not increased in Finland, as in many other developed countries. The rate of extremely preterm births has even decreased. While other risk factors of preterm birth, such as multiplicity and smoking during pregnancy have decreased, surgical treatments of the uterine cervix have become more important risk factors as regards preterm birth. Cervical conization is a predisposing factor as regards preterm birth, low birth weight and even perinatal mortality. The most frequently used treatment modality, Loop conization, is also associated with the increased risk of preterm birth. Treatments should be tailored individually; low-grade lesions should not be treated at all among young women. The first treatment should be curative, because repeat treatments are especially harmful. The proportion of IVF deliveries was not increased after treatment for CIN, suggesting that current treatment modalities do not strongly impair fertility. The long-term risk of cervical cancer remains high even after many years post-treatment; therefore careful surveillance is necessary. In addition, accidental deaths and deaths from injury were common among treated women, suggesting risk-taking behavior of these women. Preterm birth seems be associated with extremely high mortality rates, due to cardiovascular, alcohol-related and injury deaths. These women could benefit from health counseling, for example encouragement in quitting smoking.
  • Rahkonen, Leena (Helsingin yliopisto, 2010)
    Premature delivery is a major cause of neonatal morbidity and mortality. The incidence of premature deliveries has increased around the world. In Finland 5.3%, or about 3,000 children per year are born prematurely, before 37 weeks of gestation. The corresponding figure in the United States is about 13%. The morbidity and mortality are highest among infants delivered before 32 weeks of gestation - about 600 children each year in Finland. Approximately 70% of premature deliveries are unexplained. Preterm delivery can be caused by an asympto-matic infection between uterus and the fetal membranes, such can begin already in early pregnancy. It is difficult to predict preterm delivery, and many patients are therefore unnecessarily admitted to hospital for observation and exposed to medical treatments. On the other hand, the high risk women should be identified early for the best treatment of the mother and preterm infant. --- In the prospective study conducted at the Department of Obstetric and Gynecology, Helsinki University Central Hospital two biochemical inflammation related markers were measured in the lower genital tract fluids of asymp-tomatic women in early and mid pregnancy in an order to see whether these markers could identify women with an increased risk of preterm delivery. These biomarkers were phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) and matrix metalloproteinase-8 (MMP-8). The study involved 5180 asymptomatic pregnant women, examined during the first and second ultrasound screening visits. The study samples were taken from the vagina and cervicix. In addition, 246 symptomatic women were studied (pregnancy weeks 22 – 34). The study showed that increased phIGFBP-1 concentration in cervical canal fluid in early pregnancy increased the risk for preterm delivery. The risk for very premature birth (before 32 weeks of gestation) was nearly four-fold. Low MMP-8 concentration in mid pregnancy increased the risk of subsequent premature preterm rupture of fetal membranes (PPROM). Significantly high MMP-8 concentrations in the cervical fluid increased the risk for prema-ture delivery initiated by preterm labour with intact membranes. Among women with preterm contractions the shortened cervical length measured by ultrasound and elevated cervical fluid phIGFBP-1 both predicted premature delivery. In summary, because of the relatively low sensitivity of cervical fluid phIGFBP-1 this biomarker is not suitable for routine screening, but provides an additional tool in assessing the risk of preterm delivery. Cervical fluid MMP-8 is not useful in early or mid pregnancy in predicting premature delivery because of its dual role. Further studies on the role of MMP-8 are therefore needed. Our study confirms that phIGFBP-1 testing is useful in predicting pre-term delivery.
  • Pallasaho, Paula (Helsingin yliopisto, 2006)
    Objectives: To assess the prevalence and risk factor profiles of respiratory symptoms, asthma and chronic bronchitis in Helsinki, and to compare these results with those for Sweden and Estonia. Other important aims were to evaluate the prevalence and determinants of type 1 sensitization in Helsinki. Materials and methods: This presentation is a part of a large epidemiological study in Finland, Estonia and Sweden (FinEsS). The first part of the study consisted of a postal questionnaire in 1995-1996 distributed to subjects in eight study centres. The study population in each centre was a population-based random sample designed to be representative of the general population. The original study sample in Helsinki consisted of 8000 subjects aged 20-69 years, 6062 (76%) of whom participated. Comparisons between countries were based on a narrower age group, 20-64 years, since 64 years was the upper age limit used in the original study in Estonia. Thus, altogether 58 661 subjects aged 20-64 years were invited to participate in Finland, Sweden and Estonia, and 44 483 (76%) did so. The second part of the study was a clinical study with a structured interview, lung function measurements and skin-prick tests with 15 common allergens. This thesis reports only the results of the prick tests in Helsinki. Of the 1200 subjects invited to participate in Helsinki, 643 (54%) consented. Skin-prick tests were performed on subjects ≤ 60 years of age; thus, a total of 498 tests were done. Results: In Helsinki, the prevalence of physician-diagnosed asthma was 6.6% and of physician-diagnosed chronic bronchitis 3.7% among subjects aged 20-69 years. Comparison of the results between Finland, Sweden and Estonia in subjects 20-64 years of age revealed the highest prevalence of physician-diagnosed asthma in Sweden, 7.8%, while the prevalence in Finland was 5.9% and in Estonia 2.0% (p<0.001). The prevalence of physician-diagnosed asthma among those aged 20-29 years was 7.9% in Stockholm, 6.3% in Helsinki and 2.8% in Tallinn. Asthma-related symptoms were most common in Estonia, and among those with typical asthma symptoms the diagnosis of asthma was least likely in Estonia. Physician-diagnosed chronic bronchitis was reported to be 10.7% in Estonia, 3.1% in Sweden and 2.9% in Finland among subjects aged 20-64 years (p<0.001). Among those aged 20-29 years, 7.6% in Tallinn reported physician-diagnosed chronic bronchitis, while the prevalence estimates were 1.4% in Stockholm and 1.3% in Helsinki. The prevalence of smoking was similar for women in all three countries, around 30%, but large differences in smoking habits were present among men; 60% of Estonian, 39% of Finnish and 28% of Swedish men smoked. Skin-prick tests in Helsinki revealed a high prevalence of sensitization, 46.9%. For subjects aged 26-39 years, the prevalence was highest, 56.8%, and 23.7% were sensitized to at least four allergens. The most common sensitizing allergen was the dog. Sensitization to multiple allergens was associated with a high prevalence of asthma and allergic rhinitis. Conclusions: Compared with earlier Finnish studies, a higher prevalence of asthma and a lower prevalence of chronic bronchitis were found in Helsinki. The prevalence of physician-diagnosed chronic bronchitis was low in Helsinki, with only one-fifth of subjects fulfilling the symptom criteria for chronic bronchitis reporting having a diagnosis of chronic bronchitis. The prevalences of asthma and chronic bronchitis were similar in Finland and Sweden, but in Estonia physician-diagnosed asthma was less common and physician-diagnosed chronic bronchitis more common, particularly among young subjects. Further analyses revealed that the diagnosis of asthma was favoured in Finland and Sweden, while the diagnosis of chronic bronchitis was more likely in Estonia for subjects with the same symptoms. Allergic sensitization was common in Helsinki. Our findings of multiple sensitization also speak in favour of evaluating the degree of sensitization when assessing allergies.
  • Norja, Päivi (Helsingin yliopisto, 2012)
    Parvoviruses are minute single-stranded DNA viruses that infect a wide range of mammalians and invertebrates. Human parvovirus B19 (B19V) was discovered in the 1970s and was soon found to cause several diseases, including erythema infectiosum, arthropathy, anemias, fetal hydrops, and fetal death. The B19V titer in blood is high during acute infection. After primary infection, B19V has been shown to persist in tissues of symptomatic and asymptomatic persons. Prior to the commencement of this work, two new genotypes were identified for B19V that had long been considered to be very stable regarding its DNA sequence. The newly found variants are named genotype 2 and genotype 3, and the prototypic virus is genotype 1. The new genotypes were found from the blood of a child with aplastic anemia and from human skin. The most common transmission route of B19V is the respiratory tract but transmission via plasma-derived medical products also occurs. To ensure the safety of medical blood products in the European Union, new instructions were given in 2004 for B19V levels in plasma pools. These necessitate quantitative PCR (qPCR) screening for B19V DNA. Two commercially available quantitative PCR tests (qPCR A and qPCR B) existed at the beginning of this thesis project and were examined here for their ability to amplify, quantify, and differentiate B19V genotypes. qPCR A was highly sensitive for the detection of B19V genotype 1, but failed to detect B19V genotype 2 and to differentiate genotypes. qPCR B proved to be a sensitive and suitable method for detection, quantification, and differentiation of all B19V genotypes. The prevalences of B19V genotypes were examined in a large number of blood and tissue samples. B19V genotype 1 was found in 23% of maxipools of blood donor plasma, and in 17% of single samples of serum whilst no genotype 2 or 3 DNAs were detected. Various types of tissue samples contained B19V DNA of genotype 1 or genotype 2 DNA, while B19V genotype 3 DNA was absent from all the tissues studied. When grouping tissue donors according to their age, a variety in distribution of B19V genotypes was noticed. B19V genotype 1 DNA was found in all age groups, whereas genotype 2 was confined to those subjects born before 1973. Correspondingly, sera from the past two decades contained no B19V genotype 2 DNA. The results suggest that actually the newly found B19V genotype 2 is older in occurrence than the prototypic B19V genotype 1 and it has disappeared from global circulation. Furthermore, the results disclosed that persistence of B19V DNA in human tissues is lifelong and represents a source of information from our past, termed the Bioportfolio. The evolution rates of both persistent and acute B19V genomes were determined in collaboration with a British group at University of Edinburgh. As a sequencing target, the gene for viral capsid protein VP2 was amplified from serum samples collected from subjects with B19V acute infection. In comparison, the VP2 gene was amplified from tissues of subjects with serologically confirmed past B19V infection. Notably rapid sequence changes of 4x10-4 substitutions/site/year were observed in plasma-derived B19V genomes. In contrast, the evolution rate of B19Vs found in tissues was 10 times slower. In 2005, two new human parvoviruses, human bocavirus 1 (HBoV1) and human parvovirus 4 (PARV4), were discovered by molecular screening and large-scale sequencing. HBoV1 has since been shown to cause systemic infection and respiratory illness in young children. PARV4 has mainly been restricted to those with a history of intravenous drug use with the exception of Sub-Saharan Africa. Later, in 2009 and 2010, three more human bocaviruses, probably enteric viruses, were found from feces. Whether these newly found human parvoviruses share the ability of B19V to persist in human tissues, was studied. Tonsillar, synovial, and dermal tissues were examined for DNAs of these new parvoviruses; neither HBoV2-4 nor PARV4 DNAs were detected. HBoV1 DNA was found in tonsillar tissue but not in synovia or skin. HBoV1 DNA prevalence was 9 % of samples collected from young children. None of the HBoV1 IgG seropositive adults harbored HBoV1 DNA. Rather than long term persistence, the results indicate a slow evanescence of HBoV1 genomes in tonsillar tissue of children after primary exposure. With the collaboration of a German group in Regensburg, the role of B19V DNA persistence in cardiomyopathy or myocarditis was studied. The B19V DNA prevalence was 85%. B19V genotype 1 and 2 DNAs were found in 9% and 76% of heart examined, respectively. Genotype 3 was absent from all the tissues studied. The presence of B19V DNA in human heart biopsies demonstrated no correlation with clinical symptoms. Quantitative PCR methods for B19V detection in plasma-derived medical products are crucial for ensuring the viral purity of the blood products. Today, quantitative B19V PCR alone, or together with antibody assays, is commonly used in diagnosis of B19V infections. Evolution studies of parvoviruses have given us a new and unexpected perspective to rates of evolution of single-stranded DNA viruses. The ability of B19V to persist lifelong in several types of human tissues is unique among parvoviruses; human bocaviruses are not suggested to occur in solid tissues for life. The detection of B19V DNA in human heart did not indicate the pathogenesis of persistent B19V, but neither answered the question about possiblility of B19V reactivation. With known mechanism, and in light of full-length coding potential of the persistent viral DNA genomes, the persistence of B19V could, in future, provide the desired long-term permanence for gene therapy vectors. Furthermore, the persistency provides, at the global and epidemiological level, a database for analysis the occurrence and circulation of parvoviruses and their variants.
  • Ortiz Martínez, Pilar (Helsingin yliopisto, 2010)
    Enteropathogenic Yersinia can enter the food chain and infect consumers via pork. Although yersiniosis is the third most common bacterial enteric disease in Europe, there has been a lack of studies concerning the prevalence and bioserotypes of enteropathogenic Yersinia in pigs from European countries. This study was conducted in order to gain further information on the prevalence of enteropathogenic Yersinia in pigs from separate European countries. In order to examine the transmission routes of enteropathogenic Yersinia in the pork production chain from the farm to the slaughterhouse, enteropathogenic Yersinia strains were characterised in Finland by PFGE. Because the conditions on a farm can affect the prevalence of enteropathogenic Yersinia, possible farm factors associated with Yersinia prevalence were also investigated by using a questionnaire and on-farm observations. Pathogenic Yersinia enterocolitica was a common finding among all European countries included in the study. The highest (93%) and lowest (32%) prevalence of pathogenic Y. enterocolitica was observed among pigs from Spain and Italy, respectively. The prevalence in Estonia and Latvia in Northern Europe was lower than in Spain, but still at a high level of 89% and 64%, respectively, among pigs. The Leningrad region of Russia showed one of the lowest prevalence among the studied European countries. In addition, pathogenic Y. enterocolitica was present among 44% of pigs from Belgium and England or Central Europe and Western, respectively. The highest prevalence of Yersinia pseudotuberculosis was detected among English pigs (18%). Furthermore, 7%, 5% and 2% of pigs examined from the Leningrad region of Russia, Latvia and Belgium, respectively, and 1% in Italy and Estonia were positive for Y. pseudotuberculosis. Cold enrichment for 7 and 14 days combined was a more efficient method to isolate enteropathogenic Yersinia when compared to selective enrichment. The most common human pathogenic bioserotype 4/O:3 of Y. enterocolitica was also present in all studied European countries, predominating among Belgian (91%), Estonian (100%), Italian (99%), Latvian (100%), Russian (100%) and Spanish (100%) pigs, but not among English pigs (11%). In England, the most common human pathogenic bioserotypes of Y. enterocolitica were 2/O:9 (33%) and 2/O:5 (26%). Y. enterocolitica bioserotype 2/O:5 was also found among Italian (1%) pigs. In addition, less frequently isolated European human pathogenic bioserotypes 2/O:3 and 3/O:3 were respectively found in 7% and 0.3% of pigs from England, and 3/O:9 in 9% of pigs from Belgium. Bioserotype 2/O:3 of Y. pseudotuberculosis, the most commonly isolated type in pigs in Finland, predominated among Belgian (60%), English (34%), Estonian (100%), Latvian (100%) and Russian (100%) pigs, and was present among Italian pigs (20%). Bioserotypes such as 1/O:1, 1/O:2, 1/O:3, 1/O:4, 2/O:1, 2/O:5 and 3/O:3 were also found. Y. pseudotuberculosis 1/O:1 was predominant in Italy (60%), and also found in England (26%) and Belgium (20%). Y. pseudotuberculosis 1/O:2 was isolated from Belgian (20%) and English (7%) pigs. Bioserotypes 1/O:3 (5%), 1/O:4 (24%), 2/O:1 (3%), 2/O:5 (1%) and 3/O:3 (1%) were additionally found in England, showing the highest diversity of different bioserotypes in this country. In Finland, only bioserotype 4/O:3 of Y. enterocolitica and 2/O:3 of Y. pseudotuberculosis were isolated. Undistinguishable genotypes of Y. enterocolitica and Y. pseudotuberculosis isolated from a farm and a slaughterhouse indicated that carcass contamination has its origin on the farm and enteropathogenic Yersinia is transported with the pig to the slaughterhouse. Based on Y. enterocolitica genotypes, Y. enterocolitica-positive pigs are contaminating pluck sets, and pluck sets can also be contaminated with Y. enterocolitica from other sources in the slaughterhouse. Factors associated with the high prevalence of Y. enterocolitica on farms according to correlation and two-level logistic regression analysis were drinking from a nipple, the absence of coarse feed or bedding for slaughter pigs, and no access of pest animals to the pig house. Those farms with an organic or low-production capacity showed a lower prevalence than high-production capacity conventional farms. Farm factors associated with the presence of Y. pseudotuberculosis in Finnish farms were contact with pest animals and the outside environment and a rise in the number of pigs on the farm. Organic production farms had a higher prevalence than conventional farms.
  • Leinonen, Maarit (Helsingin yliopisto, 2013)
    A randomised trial on alternative screening methods implemented in the organised cervical cancer screening programme has been running in Finland since 1999. In this trial, screening with an automation assisted cytology and screening with a primary HPV DNA test (the latter since 2003) is compared to screening with a conventional cytology (Pap test). The ultimate aim of the trial is to assess the incidence of cervical precancerous lesions and cancer following the initial screening visit. This setting enables to evaluate the effectiveness of screening using different screening modalities. The aim of this study was to study the prevalence of the carcinogenic cervical HPV infection in Finland and to evaluate the use of an HPV DNA test in cervical cancer screening as a primary screening test. A cytology triage followed for women who were found to be HPV DNA-positive. HPV DNA-positive women were then referred to colposcopy based on the cytology triage result, similarly as in the conventional protocol. Performance and validity of a primary HPV DNA test with cytology triage in comparison with a conventional cytology was evaluated both in a cross-sectional and in a prospective setting. Screening methods were compared by measuring following crosssectional parameters at the initial (index) screening: test positivity, recommendation to intensive screening, referral to colposcopy and histological detection rates. We also estimated relative sensitivity, relative specificity and positive predictive values of the screening methods for different histological outcomes. Effects of screening methods on the burden of precancerous lesions and cancer were studied also in a longitudinal followup design. We analysed hazard ratios between study arms and cumulative hazards of cervical lesion for the different histological outcomes from the prospective data. The majority of the cervical precancerous lesions in Finland are currently detected outside the national programme. Thus, the effectiveness of screening in the Finnish female population cannot be completely evaluated from the cervical lesions detected only within the screening programme. Therefore, we used data from the screening register and appended it by retrieving cervical lesions also from the Finnish Cancer Registry and from the Care Registers for Social Welfare and Health Care (formerly the Finnish Hospital Discharge Register, HDR) maintained by the THL. These registers included also lesions that were detected outside the national screening programme. Our study showed a similar inverse relationship between the prevalence of carcinogenic HPV infection (high-risk HPV, hrHPV) and age reported in other developed countries. Age was found to be a strong determinant of hrHPV infection. Other significant risk factors included marital status and a previous hysterectomy. Prevalence rate of any hrHPV infection reflects the background risk for cervical cancer. It was at the same level, or at least it was not markedly lower than in other European countries. This indicates that the low burden of cervical cancer is due to the health care actions including free public screenings within the organised programme. Type-specific HPV prevalence was somewhat lower than suggested by international meta-analyses. The most common hrHPV type was HPV 16 followed by 31 and 52. The distribution of the hrHPV types in Finland was closest to reports from Eastern Europe suggesting that HPV types found in Finland are consistent with a regional HPV type distribution in the world. HPV 16 attributed one fifth of the referrals to colposcopy but caused clearly more than half of the most severe cervical precancerous lesions and cancers(CIN 3+). At the index screen visit, there were equal numbers of colposcopies in both study arms. However, screening by the HPV DNA test detected significantly more mild and moderate cervical lesions (CIN 1 and CIN 2) in comparison with screening by the cytology. The relative specificity and the positive predictive value (PPV) of the HPV DNA test alone were inferior to cytology. However, the relative specificity of the HPV DNA test with cytology triage was similar and even slightly better than that of cytology among women 35 years and older. The PPVs of the HPV DNA test with cytology triage were consistently better than those of conventional screening. Recommendations to intensive screening were made more often in the HPV than in the conventional arm. This was mainly due to the low age of the screening population (< 35 years). During one screening round of five years, the HPV test identified women at risk for severe cervical precancerous lesion or cancer (CIN 3+) markedly better than cytology. The cumulative detection rates of cervical lesions over one screening round showed that a very few cases of CIN 3 or AIS were diagnosed later than three and a half years after an invitation to an HPV screening arm among women aged 35 years and older. On the contrary, there was a rather constant increase in the detection of CIN 3 or AIS in the conventional screening arm between the years of two and five following the initial screening. This difference between the screening arms suggests an opportunity for earlier diagnosis of high-grade cervical lesions if HPV DNA test would be used used as a routine screening test. After a negative HPV DNA test result (92% of the screened), there were substantially less CIN 3+ cases detected than after a normal result in cytology (93% of the screened) at the index screen visit. This indicates that HPV-based screening better identifies women with whom an extended screening interval would be safe. This could potentially reduce the screening demand for a large group of women and thus result in significant cost savings. In a population-based screening programme, most women are healthy. Also, CIN 3 and cancer are rare outcomes in well-screened populations. This necessitates a careful balance between sensitivity and specificity of the screening tests. On the other hand, when the outcome is rare, there is then less potential for new interventions to improve prevention. Thus, more aggressive protocols might be warranted to increase the effectiveness of screening. An important issue in HPV screening is how to manage HPV-positive women. Intensive surveillance with frequent colposcopies may easily result in overdiagnosis and overtreatment of cervical lesions. This in turn may have economical and psychosocial consequences and result in morbidity for women of reproductive age. When the HPV DNA test is considered as a measure for routine use, then age groups and screening intervals need to be carefully selected. This applies particularly to the algorithm that follows a positive HPV DNA test result. HPV testing should only be done within the organised screening programme whilst a gradual implementation of HPV screening in other regions in Finland would be preferred. This allows for systematical evaluation of possible adverse effects and the effectiveness of screening.
  • Nihtinen, Anne (Helsingin yliopisto, 2012)
    Invasive fungal infections constitute a potentially lethal complication in patients with acute leukaemia and in allogeneic stem cell transplant (SCT) recipients. The poor prognosis is associated with delays in the diagnosis of these infections. Colonization of the mucous membranes is the first step in the pathogenesis of IFI. With Candida infections the colonization occurs in the gastrointestinal tract. Aspergillus spores enter the body from the air to the lungs. Air filtration reduces the number of spores in the air and the risk of invasive aspergillosis (IA). The studies in this thesis had their focus on the prevention and serological diagnostic methods of IA and invasive candidiasis (IC). The following factors were investigated in 102 adult allogeneic SCT recipients transplanted in 2001-2002: nasal colonization with Aspergillus species, oral colonization with Candida species, the feasibility of two antigen tests (Aspergillus galactomannan and Candida mannan) as diagnostic tools, and the incidence of IA and IC. Simultaneously with the patient sampling, environmental samples were obtained from the HEPA-filtered SCT ward to asses the role of environmental exposure to moulds as a risk factor for IA. Nasal samples yielded positive results in three patients. Two patients had IA. Of the 2071 serum samples, 12 (0.6%) yielded positive results with the galactomannan antigen test in nine patients (8.8%). One of these patients had IA. The oral samples yielded positive results in 38 patients but only one patient had IC. In this patient, the Candida mannan test yielded the first positive result seven weeks before the infection. Single false positive test results were common; they were detected in 54 patients. False results were associated with the use of acyclovir and valacyclovir. Aspergillus species were detected in only 6.1% of the environmental samples. The air quality also remained good during a period of heavy construction activity in the immediate vicinity of the SCT ward. Such periods can cause outbreaks of IA. Fluconazole prophylaxis was assessed in 1089 adult patients with acute leukaemia by comparing the incidence of IC in 847 patients not receiving prophylaxis (years 1978-1999) to 242 patients receiving fluconazole prophylaxis (years 2000-2004). The incidence of IC was 8.7% and 1.6% (P less than 0.001). The efficacy of Amphotericin B (AmB) inhalation prophylaxis was analysed in allogeneic SCT recipients. Antifungal prophylaxis was not given to 257 patients transplanted in 1996-2000 (Period I). In the 354 patients transplanted in 2001-2005 (Period II) AmB inhalation prophylaxis was started in cases of acute graft-versus-host disease requiring therapy with high-dose methylprednisolone. IA was detected in 17 (6.6%) vs. 9 (2.5%) of the patients in Period I and Period II (P = 0.007).
  • Nurmi, Katariina (Helsingin yliopisto, 2015)
    The innate immune system responds to infection or injury by initiating nonspecific inflammation, which functions to limit the spread of harmful microbes or the damage caused by tissue injury. The cells of the innate immune system are the first to encounter danger signals, and they mediate the rapid local immune response. Inflammatory reactions are normally beneficial for the host, and inflammation is usually resolved when the threat has been removed. However, in chronic inflammatory diseases, the danger signals either are not cleared or continue to be formed. Pathogen-derived molecules and danger signals induce the activation of pattern recognition receptors (PRRs) in the innate immune cells. Several families of PRRs exist, and their interplay is needed for the induction of efficient immune defense reactions. Nucleotide-binding domain and leucine-rich repeat-containing receptors (NLRs) are intracellular receptors that respond to a plethora of danger- and pathogen-associated molecular patterns. Their activation induces the assembly and activation of cytosolic multiprotein complexes called inflammasomes. Inflammasomes act as a primary checkpoint for the activation and secretion of the strong proinflammatory cytokines interleukin (IL)-1β and IL-18. Similar to other cellular functions, innate immune responses are operated via a complicated interplay between signalosomes. To become activated inflammasomes require the coordinated activation of Toll-like receptors (TLRs) and NLRs, which induce the activation and assembly of inflammasome complexes. The consequent secretion of inflammasome-derived cytokines is, in turn, modulated by autophagy. Inflammasome activation and autophagy also interact with cellular death pathways. Cellular death acts to limit the spread of intracellular pathogens by denying a protective niche to these pathogens, thereby inhibiting their replication and predisposing them for detection by the immune system. The aim of this study was to investigate the roles of ethanol and hemin in the modulation of innate immune cell functions, as well as the mechanisms underlying the reported protective effects of ethanol and hemin against chronic inflammatory diseases. Alcohol is the most commonly and widely used drug in the world. The consequences of alcohol consumption depend on both the pattern of consumption and the amounts consumed. Alcohol abuse predisposes to more frequent and severe infections, whereas the light to moderate consumption of alcoholic beverages has been associated with a reduced incidence of chronic inflammatory conditions, such as cardiovascular diseases and rheumatoid arthritis. These seemingly different responses may both derive from attenuated reactions of innate immunity. In the present thesis study, ethanol was shown to reduce the viability and proliferation of mast cells. This reduced viability resulted from the immunologically silent apoptotic death of mast cells. In macrophages, ethanol reduced the pyroptotic cell death induced by inflammasome activation and instead directed cell death toward apoptosis. Excessive inflammasome activation is a prominent feature of several chronic inflammatory diseases. The mechanisms that restrain inflammasome activation were studied in greater detail in cultured macrophages. Ethanol dose-dependently inhibited inflammasome activation and the secretion of IL-1β in human macrophages. It was further shown that the inhibitory effect of ethanol was mediated by a reduction in lysosomal disruption and the release of active cathepsin B, which thus contributed to diminished inflammasome assembly. The majority of mammalian cells are constantly renewed. Enormous numbers of senescent red blood cells are phagocytosed daily by macrophages. In certain pathologies, such as malarial infection, massive hemolysis occurs that exceeds the capacity of the scavenging and degradation systems of hemoglobin. As a consequence, free heme and hemin are released into the circulation. Free heme and hemin are cytotoxic and proinflammatory compounds. However, heme and hemin are also potent inducers of the heme oxygenase-1 (HO-1) enzyme, which possesses anti-inflammatory and cytoprotective effects. In the present thesis study, hemin and its synthetic derivative cobalt protoporphyrin (CoPP) blocked inflammasome activation and assembly. Decreased secretion of IL-1β was also observed in vivo in a nucleotide-binding domain and leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3)-dependent peritonitis model in mice. The inhibitory effects of hemin and CoPP were partially dependent on the induction of HO-1 transcription by NF-E2-related factor-2 (Nrf2) and the enzymatic activity of HO-1. The inhibitory effects of hemin and CoPP were mediated by increased degradation of inflammasome components, which was due to elevated autophagy. Overall, the results of this study demonstrate that ethanol and hemin markedly prevent inflammatory cellular responses in macrophages and mast cells. This inhibition may contribute to the cardioprotective effect of ethanol and the anti-inflammatory effects of hemin. An enhanced molecular understanding of the mechanisms by which ethanol and hemin inhibit inflammation may help reveal new therapeutic options in the treatment of chronic inflammatory diseases.
  • Lindström, Jaana (Helsingin yliopisto, 2006)
    Type 2 diabetes is an increasing, serious, and costly public health problem. The increase in the prevalence of the disease can mainly be attributed to changing lifestyles leading to physical inactivity, overweight, and obesity. These lifestyle-related risk factors offer also a possibility for preventive interventions. Until recently, proper evidence regarding the prevention of type 2 diabetes has been virtually missing. To be cost-effective, intensive interventions to prevent type 2 diabetes should be directed to people at an increased risk of the disease. The aim of this series of studies was to investigate whether type 2 diabetes can be prevented by lifestyle intervention in high-risk individuals, and to develop a practical method to identify individuals who are at high risk of type 2 diabetes and would benefit from such an intervention. To study the effect of lifestyle intervention on diabetes risk, we recruited 522 volunteer, middle-aged (aged 40 - 64 at baseline), overweight (body mass index > 25 kg/m2) men (n = 172) and women (n = 350) with impaired glucose tolerance to the Diabetes Prevention Study (DPS). The participants were randomly allocated either to the intensive lifestyle intervention group or the control group. The control group received general dietary and exercise advice at baseline, and had annual physician's examination. The participants in the intervention group received, in addition, individualised dietary counselling by a nutritionist. They were also offered circuit-type resistance training sessions and were advised to increase overall physical activity. The intervention goals were to reduce body weight (5% or more reduction from baseline weight), limit dietary fat (< 30% of total energy consumed) and saturated fat (< 10% of total energy consumed), and to increase dietary fibre intake (15 g / 1000 kcal or more) and physical activity (≥ 30 minutes/day). Diabetes status was assessed annually by a repeated 75 g oral glucose tolerance testing. First analysis on end-points was completed after a mean follow-up of 3.2 years, and the intervention phase was terminated after a mean duration of 3.9 years. After that, the study participants continued to visit the study clinics for the annual examinations, for a mean of 3 years. The intervention group showed significantly greater improvement in each intervention goal. After 1 and 3 years, mean weight reductions were 4.5 and 3.5 kg in the intervention group and 1.0 kg and 0.9 kg in the control group. Cardiovascular risk factors improved more in the intervention group. After a mean follow-up of 3.2 years, the risk of diabetes was reduced by 58% in the intervention group compared with the control group. The reduction in the incidence of diabetes was directly associated with achieved lifestyle goals. Furthermore, those who consumed moderate-fat, high-fibre diet achieved the largest weight reduction and, even after adjustment for weight reduction, the lowest diabetes risk during the intervention period. After discontinuation of the counselling, the differences in lifestyle variables between the groups still remained favourable for the intervention group. During the post-intervention follow-up period of 3 years, the risk of diabetes was still 36% lower among the former intervention group participants, compared with the former control group participants. To develop a simple screening tool to identify individuals who are at high risk of type 2 diabetes, follow-up data of two population-based cohorts of 35-64 year old men and women was used. The National FINRISK Study 1987 cohort (model development data) included 4435 subjects, with 182 new drug-treated cases of diabetes identified during ten years, and the FINRISK Study 1992 cohort (model validation data) included 4615 subjects, with 67 new cases of drug-treated diabetes during five years, ascertained using the Social Insurance Institution's Drug register. Baseline age, body mass index, waist circumference, history of antihypertensive drug treatment and high blood glucose, physical activity and daily consumption of fruits, berries or vegetables were selected into the risk score as categorical variables. In the 1987 cohort the optimal cut-off point of the risk score identified 78% of those who got diabetes during the follow-up (= sensitivity of the test) and 77% of those who remained free of diabetes (= specificity of the test). In the 1992 cohort the risk score performed equally well. The final Finnish Diabetes Risk Score (FINDRISC) form includes, in addition to the predictors of the model, a question about family history of diabetes and the age category of over 64 years. When applied to the DPS population, the baseline FINDRISC value was associated with diabetes risk among the control group participants only, indicating that the intensive lifestyle intervention given to the intervention group participants abolished the diabetes risk associated with baseline risk factors. In conclusion, the intensive lifestyle intervention produced long-term beneficial changes in diet, physical activity, body weight, and cardiovascular risk factors, and reduced diabetes risk. Furthermore, the effects of the intervention were sustained after the intervention was discontinued. The FINDRISC proved to be a simple, fast, inexpensive, non-invasive, and reliable tool to identify individuals at high risk of type 2 diabetes. The use of FINDRISC to identify high-risk subjects, followed by lifestyle intervention, provides a feasible scheme in preventing type 2 diabetes, which could be implemented in the primary health care system.
  • Khami, Mohammad Reza (Helsingin yliopisto, 2007)
    The present study investigated the preventive orientation of the dental education system in Iran as reflected in the responses of dental school educators and dental students to a questionnaire survey. Two questionnaires, one for dental school educators and one for senior dental students, were designed and piloted. Of the 15 state dental schools in Iran, 7 were selected using a multi-stage sampling approach, and all the dental school educators and senior dental students in these schools were asked to voluntarily fill in the anonymous questionnaires. Totally, 291 educators (80%) and 270 students (82%) participated in the study. In addition to background information, both questionnaires requested information on knowledge of caries prevention, attitudes towards preventive dentistry and oral health behaviour of the respondents. The students' questionnaire also covered items concerning prevention-oriented practice, study motives, and career preferences. Contrary to knowledge and attitudes of the students, those of the educators' were positively associated with some of their academic and personal background characteristics. Women were more likely to report favourable oral self-care habits than men. The other determinants of oral health behaviour were educators' familiarity with the oral public health field, and students' attitudes towards prevention. A higher score on preventive practice among the students was associated with better oral self-care habits and positive attitudes towards prevention. Characteristics of the profession and social status and security were the top-ranked that motivated students to study dentistry, and students mainly preferred to enter postgraduate courses and private practice after graduation. To increase the orientation of Iran's health care system towards prevention, and to cope with current concepts of prevention, corresponding changes should be made in the dental education system. The results of this study support the revision of the dental curriculum by placing more emphasis on prevention-related topics and by integrating prevention-related concepts into all disciplines. Additionally, practicing dentists and dental educators should be provided with opportunities to attend continuing education courses and to conduct seminars and congresses on various aspects of preventive dentistry at home as well as abroad.
  • Tseveenjav, Battsetseg (Helsingin yliopisto, 2004)