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  • 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).
  • 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)
  • Ghasemi, Hadi (Helsingin yliopisto, 2008)
    The present study investigated the preventive orientation of Iranian dentists and what they perceived as barriers to the provision of preventive dental care. The target population comprised Iranian general dental practitioners that took part in two major dental congresses in Tehran, Iran, one in December 2004, and the other in July 2005. Data was gathered by means of a self-administered questionnaire which was filled in anonymously. The questionnaire covered dentists' knowledge of caries prevention, attitudes towards preventive dental care, self-assessed oral health behaviour, restorative treatment threshold, risk-based preventive practice, involvement in smoking cessation, perceived barriers for carrying out preventive dental care, practice-related information, activity in continuing education and background information. In total, 1033 dentists completed the questionnaire, and 980 were eligible for the present study; their mean age was 37.3 years, and 64% were men. The dentists showed high levels of knowledge of and positive attitudes towards preventive dental care. They, however, underestimated the role of fluoride toothpaste. More than half the dentists complied with the optimal level of oral self-care and almost half reported having visited a dentist for a routine dental check-up during the last year. There was a strong tendency among the dentists to intervene in proximal enamel caries restoratively. The majority of the dentists agreed with applying well-known preventive measures, and more than half reported that they always recommend that a smoking patient quit the habit. Dentists’ level of preventive input was positively correlated with their knowledge of and attitudes towards preventive dental care. Moreover, this correlation was evident regarding the dentists’ activities for their own oral health. Patient-related factors were the most frequently cited barrier among these dentists for the provision of preventive dental care. Generally, female dentists demonstrated a stronger preventive orientation than did male dentists. It can be concluded that there is room for improvement in dentists' knowledge of and attitudes towards preventive dental care, and this requires placing more emphasis on relevant areas in dental education. More understanding of barriers to the provision of preventive dental care is required to facilitate dentists' preventive practice.
  • Ikonen, Annukka (Helsingin yliopisto, 2012)
    ABSTRACT In Finland, most employers offer primary care for their employees in addition to the preventive occupational health services (OHS). The purpose of this study was to determine the role of OHS in the health care of working persons as well as the relationship between primary care visits to OHS and prevention and work-related factors. The study showed that over 50% of employees used only OHS for primary care and the use of public health care was reduced. Men seemed to favour OHS as a primary health care provider. The proportion of visits to occupational health (OH) physicians was found to have increased compared to other OH professionals. Mental health problems, musculoskeletal disorders, chronic illnesses impairing work ability, and poor work ability were associated with visits to OHS but still about half of the employees with these problems did not use OHS. The role of OH nurses seemed important in detecting insomnia, burnout, and depressive disorders. Work-related symptoms and work ability were found to be frequently examined during OHS primary care visits. Over half of the visits to OH physicians were work-related when the reason for consulting was at least partially due to work or when the need for sickness absence was considered. Workplace harassment and lack of influence on one s work was associated with visits to OH nurses or physicians, indicating that they have the possibility to gain knowledge about work-related factors through primary care visits. Employers requirements of sickness certificates covering the first day of sickness were associated with visiting OHS among men. The role of supervisors in controlling short sickness absences could be emphasized. Although health promotion and interventions aimed at work were carried out in primary care visits to OH physicians, interventions aimed at workplaces could be increased. In conclusion, OHS primary care contributes to preventive activities and is often interrelated with employees work and work ability.
  • Riska, Annika (Helsingin yliopisto, 2007)
    The aim of the study was to clarify the occurrence, and etiological and prognostic factors of primary fallopian tube carcinoma (PFTC). We studied the sociodemographic determinants of the incidence of PFTC in Finland and the role of chlamydial infections and human papillomavirus infections as risk factors for PFTC. Serum tumor markers were studied as prognostic factors for PFTC. We also evaluated selected reproductive factors (parity, sterilization and hysterectomy) as risk or protective factors of PFTC. The risks of second primary cancers after PFTC were also studied. The age-adjusted incidence of PFTC in Finland increased to 5.4 / 1,000,000 in 1993 97. The incidence rate was higher in the cities, but the relative rise was higher in rural areas. Women in the two highest social classes showed a 1.8 fold incidence compared with those in the lowest. Women in agriculture and those not working outside the home showed only half the PFTC incidence of those in higher socioeconomic occupations. Pretreatment serum concentrations of hCGβ, CA125 and TATI were evaluated as prognostic markers for PFTC. Elevated hCGβ values (above the 75th percentile, 3.5 pmol/L; OR 2.49, 95% CI 1.22 5.09), stage and histology were strong independent prognostic factors for PFTC. The effects of parity, sterilization and hysterectomy on the risk of PFTC were studied in a case control-study with 573 PFTC cases from the Finnish Cancer Registry. In multivariate analysis parity was the only significant protective factor as regards PFTC, with increasing protection associated with increasing number of deliveries. In univariate analysis sterilization gave borderline protection against PFTC and the protective effect increased with time since the operation. In multivariate analysis the protection did not reach statistical significance. Chlamydial and human papillomavirus (HPV) infections were studied in two separate seroepidemiological case-control studies with 78 PFTC patients. The incidence of women with positive HPV or chlamydial serology was the same in PFTC patients and in the control group and was not found to be a risk factor for PFTC. Finally, the possible risk of a second primary cancer after diagnosis and treatment of PFTC in a cohort of 2084 cases from 13 cancer registries followed for second primary cancers within the period 1943 2000 was studied. In PFTC patients, second primary cancers were 36% more common than expected (SIR 1.36, 95% CI 1.13 1.63). In conclusion, the incidence of PFTC has increased in Finland, especially in higher social classes and among those in certain occupations. Elevated serum hCGβ reflect a worsened prognosis. Parity is a clear protective factor, as is previous sterilization. After PFTC there is a risk of second primary cancers, especially colorectal, breast, lung and bladder cancers and non-lymphoid leukemia. The excess of colorectal and breast cancers after PFTC may indicate common effects of earlier treatments, or they could reflect common effects of lifestyle or genetic, immunological or environmental background.
  • Mäkelä, Keijo (Helsingin yliopisto, 2010)
    The first aim of the current study was to evaluate the survival of total hip arthroplasty (THA) in patients aged 55 years and older on a nation-wide level. The second aim was to evaluate, on a nation wide-basis, the geographical variation of the incidence of primary THA for primary OA and also to identify those variables that are possibly associated with this variation. The third aim was to evaluate the effects of hospital volume: on the length of stay, on the numbers of re-admissions and on the numbers of complications of THR on population-based level in Finland. The survival of implants was analysed based on data from the Finnish Arthroplasty Register. The incidence and hospital volume data were obtained from the Hospital Discharge Register. Cementless total hip replacements had a significantly reduced risk of revision for aseptic loosening compared with cemented hip replacements. When revision for any reason was the end point in the survival analyses, there were no significant differences found between the groups. Adjusted incidence ratios of THA varied from 1.9- to 3.0-fold during the study period. Neither the average income within a region nor the morbidity index was associated with the incidence of THA. For the four categories of volume of total hip replacements performed per hospital, the length of the surgical treatment period was shorter for the highest volume group than for the lowest volume group. The odds ratio for dislocations was significantly lower in the high volume group than in the low volume group. In patients who were 55 years of age or older, the survival of cementless total hip replacements was as good as that of the cemented replacements. However, multiple wear-related revisions of the cementless cups indicate that excessive polyethylene wear was a major clinical problem with modular cementless cups. The variation in the long-term rates of survival for different cemented stems was considerable. Cementless proximal porous-coated stems were found to be a good option for elderly patients. When hip surgery was performed on with a large repertoire, the indications to perform THAs due to primary OA were tight. Socio-economic status of the patient had no apparent effect on THA rate. Specialization of hip replacements in high volume hospitals should reduce costs by significantly shortening the length of stay, and may reduce the dislocation rate.
  • Hyvärinen, Kati (Helsingin yliopisto, 2013)
    Atherosclerotic vascular diseases (ASVDs) affect the heart and circulatory system. One of the most common forms is coronary artery disease (CAD) which may eventually lead to acute coronary syndrome (ACS). ASVDs are currently the leading cause of mortality worldwide, and account for 47% of all deaths in Europe. The underlying mechanism is atherosclerosis, a progressive disease that manifests in several tissues. Common chronic infections, including periodontal disease and Chlamydia pneumoniae, may promote atherosclerosis and are associated with an increased risk of ASVDs. The general aims of this thesis project were to investigate the role of bacteria associated with periodontal disease in CAD, and the mechanisms by which common chronic infections promote proatherogenic alterations. More specifically, we aimed to: I) study the effects of Aggregatibacter actinomycetemcomitans and C. pneumoniae infections on the liver and adipose tissue lipid homeostasis and inflammation status in mice; II) develop and validate a quantitative PCR (QPCR) method to analyze the levels of periodontal disease-associated bacteria in saliva; and III) determine the association between salivary pathogen levels and CAD. The animal studies were conducted in atherosclerosis-susceptible apolipoprotein E-deficient mice. They were infected intravenously with viable A. actinomycetemcomitans and intranasally with viable C. pneumoniae. Consequently, the pathogens were recovered in the liver and C. pneumonia also in the lungs. Both infections induced systemic and hepatic inflammation, which were seen as an elevation of inflammation markers. Chronic C. pneumoniae infection induced hepatic microvesicular formations, which may promote steatosis. The recurrent A. actinomycetemcomitans infection disturbed the lipid homeostasis of adipose tissue: the proportion of saturated fatty acids was increased and that of polyunsaturated fatty acid decreased. The alterations in adipose tissue transcriptomes were depot-specific, and the inguinal adipose tissue was especially prone to inflammation-related responses. Single-copy gene-based QPCR assays were developed for five periodontal disease-associated bacteria: A. actinomycetemcomitans, Porphyromonas gingivalis, Prevotella intermedia, Treponema denticola, and Tannerella forsythia. The assays were validated in a case-control population including periodontally diseased and healthy subjects, and the diagnostic ability was found to be potent. The association of these pathogens with CAD was determined by analyzing saliva samples from the Parogene cohort (n = 492), consisting of patients with stable CAD, ACS, and no significant CAD as the reference group. All CAD diagnoses were verified by coronary angiography. The increased salivary levels of A. actinomycetemcomitans strongly associated with both stable CAD and ACS. Systemic exposure to the pathogen was seen as elevated serum antibody levels against the pathogen. The findings from the animal study indicate that A. actinomycetemcomitans and C. pneumoniae infections induce inflammation and disturbances in lipid and fatty acid homeostasis in the liver and adipose tissue. The potential tissue dysfunction may further augment the progression of atherosclerosis. The results from the Parogene study demonstrate that high salivary levels and systemic exposure to A. actinomycetemcomitans are associated with the risk of CAD and its acute manifestation. The findings from the thesis study are of common interest, because the studied pathogens are highly prevalent among the general population and their persistence may increase the overall risk of ASVDs.
  • Stamatova, Iva (Helsingin yliopisto, 2010)
    Yogurt consumption has been related to longevity of some populations living on the Balkans. Yogurt starter L. delbrueckii subsp. bulgaricus and Str. thermophilus have been recognized as probiotics with verified beneficial health effects. The oral cavity emerges as a arget for probiotic applications. Probiotics have demonstrated promising results in controlling dental diseases and oral yeast infections. However, L. bulgaricus despite its broad availability in dairy products has not been evaluated for probiotic activity in the mouth. These series of studies investigated in vitro properties of L. bulgaricus to outline its potential as an oral probiotic. Prerequisite probiotic properties in the mouth are resistance to oral defense mechanisms, adherence to saliva-coated surfaces, and inhibition of oral pathogens. L. bulgaricus strains showed a strain-dependent inhibition of oral streptococci and Aggregatibacter actinomycetemcomitans, whereas none of the dairy starter strains could affect growth of Porphyromonas gingivalis and Fusobacterium nucleatum. Adhesion is a factor contributing to colonization of the species at the target site. Radiolabeled L. bulgaricus strains and L. rhamnosus GG were tested for their ability to adhere to saliva-coated surfaces. The effects of lysozyme on adhesion and adhesion of Streptococcus sanguinis after lactobacilli pretreatment were also assessed. Adhesion of L. bulgaricus remained lower in comparison to L. rhamnosus GG. One L. bulgaricus strain showed binding frequency comparable to S. sanguinis. Lysozyme pretreatment significantly increased Lactobacillus adhesion. Low gelatinolytic activity was observed for all strains and no conversion of proMMP-9 to its active form was induced by L. bulgaricus. Safety assessment ruled out deleterious effects of L. bulgaricus on extracellular matrix structures. Cytokine response of oral epithelial cells was assessed by measuring IL-8 and TNF-α in cell culture supernatants. The effect of P. gingivalis on cytokine secretion after lactobacilli pretreatment was also assessed. A strain- and time-dependent induction of IL-8 was observed with live bacteria inducing the highest levels of cytokine secretion. Levels of TNF-α were low and only one of ten L. bulgaricus strains stimulated TNF-α secretion similar to positive control. The addition of P. gingivalis produced immediate reduction of cytokine levels within the first hours of incubation irrespective of lactobacilli strains co-cultured with epithelial cells. According to these studies strains among the L. delbrueckii subsp. bulgaricus species may have beneficial probiotic properties in the mouth. Their potential in prevention and management of common oral infectious diseases needs to be further studied.
  • Kukkonen, Anna Kaarina (Helsingin yliopisto, 2008)
    The rapid increase in allergic diseases in developed, high-income countries during recent decades is attributed to several changes in the environment such as urbanization and improved hygiene. This relative lack of microbial stimulation is connected to a delay in maturation of the infantile immune system and seems to predispose especially genetically prone infants to allergic diseases. Probiotics, which are live ingestible health-promoting microbes, may compensate for the lack of microbial stimulation of the developing gut immune system and may thus be beneficial in prevention of allergies. Prebiotics, which are indigestible nutrients by us, promote the growth and activity of a number of bacterial strains considered beneficial for the gut. In a large cohort of 1 223 infants at hereditary risk for allergies we studied in a double-blind placebo-controlled manner whether probiotics administered in early life prevent allergic diseases from developing. We also evaluated their safety and their effects on common childhood infections, vaccine antibody responses, and intestinal immune markers. Pregnant mothers used a mixture of four probiotic bacteria or a placebo, from their 36th week of gestation. Their infants received the same probiotics plus prebiotic galacto-oligosaccharides for 6 months. The 2-year follow-up consisted of clinical examinations and allergy tests, fecal and blood sampling, and regular questionnaires. Among the 925 infants participating in the 2-year follow-up the cumulative incidence of any allergic disease (food allergy, eczema, asthma, rhinitis) was comparable in the probiotic (32%) and the placebo (35%) group. However, eczema, which was the most common manifestation (88%) of all allergic diseases, occurred less frequently in the probiotic (26%) than in the placebo group (32%). The preventive effect was more pronounced against atopic (IgE-associated) eczema which, of all atopic diseases, accounted for 92%. The relative risk reduction of eczema was 26% and of atopic eczema 34%. To prevent one case of eczema, the number of mother-infant pairs needed to treat was 16. Probiotic treatment was safe without any undesirable outcome for neonatal morbidity, feeding-related behavior, serious adverse events, growth, or for vaccine-induced antibody responses. Fewer infants in the probiotic than in the placebo group received antibiotics during their first 6 months of life and thereafter to age 2 years suffered from fewer respiratory tract infections. As a novel finding, we discovered that high fecal immunoglobulin A (IgA) concentrations at age 6 months associated with reduced risk for atopic (IgE-associated) diseases by age 2 years. In conclusion, although feeding probiotics to high-risk newborn infants showed no preventive effect on the cumulative incidence of any allergic diseases by age 2, they apparently prevented eczema. This probiotic effect was more pronounced among IgE-sensitized infants. The treatment was safe and seemed to stimulate maturation of the immune system as indicated by increased resistance to respiratory infections and improved vaccine antibody responses.
  • Lehtoranta, Liisa (Helsingin yliopisto, 2012)
    Viral respiratory and gastrointestinal infections are a major health problem, in particular among children. A large range of etiologic agents and increasing antiviral and antibiotic resistance, challenge the development of efficient therapies. Accumulating evidence suggests that specific probiotic bacteria are able to decrease the risk and symptoms of these infections. This thesis investigated the effects of specific probiotics, in particular Lactobacillus rhamnosus GG, on respiratory and gastrointestinal virus infections in a cell model in vitro, in a rat model in vivo, and in children. A particular focus was on questions, whether viability of a probiotic is an important factor in probiotic-virus interaction, and whether a combination of probiotics is more effective than single strains. A novel colorimetric neutralization assay was developed for measuring influenza virus antibodies in human sera. The method was applied to measure antibody response after the administration of a seasonal, inactivated, trivalent influenza vaccine. The results were compared with those obtained with a traditional hemagglutinin inhibition test. The results obtained with both assays correlated well. Moreover, neutralization test proved to be more sensitive and specific than the hemagglutinin inhibition test. Thus, the method is valid for influenza virus research, and it could be applied for studying immune adjuvant effects of probiotics on serum influenza antibody titers in the future. Immunomodulatory effects of probiotics were screened in human macrophage model in vitro. After 24 hours of bacterial stimulation, probiotic combination of L. rhamnosus GG and L. rhamnosus Lc705 was not able to significantly induce higher macrophage cytokine and chemokine production (TNF-α, IL-1β, IL-6, IL-10, and IL-12, MCP-1, IP-10) over individual L. rhamnosus strains. However, cytokine responses induced by this combination were stronger than responses induced by traditional starter culture bacterium Lactococcus lactis ARH74, highlighting that immunomodulatory effects of probiotics are strain specific. The effects of viable and unviable L. rhamnosus GG in rotavirus infection were investigated in a neonatal rat model. Consistency of feces, animal weight, colon weight and the rotavirus colonization of plasma and intestinal tissues were considered as indexes of infection severity. Nonviable L. rhamnosus GG had beneficial effects in rotavirus infection in terms of reducing rotavirus induced body weight reduction and colon weight increase. However, viable L. rhamnosus GG was more effective in reducing significantly viral load in the gastrointestinal tract. The effects of L. rhamnosus GG alone or probiotic combination containing L. rhamnosus GG on the occurrence of viral respiratory infections was assessed in a six month intervention trial in children or in otitis-prone children. Children receiving only L. rhamnosus GG had fewer days with respiratory tract symptoms during the intervention period. However, L. rhamnosus GG did not reduce viral occurrence in the nasopharynx, suggesting that L.rhamnosus GG is able to reduce respiratory virus symptoms through enhancing immune response. In otitis-prone children, L. rhamnosus GG in a combination with L. rhamnosus Lc705, Bifidobacterium breve 99, and Propionibacterium freudenreichii ssp. shermanii JS significantly reduced human bocavirus load in the nasopharynx three to six months after intervention. In conclusion, probiotics and their combinations differ in their ability to elicit immunomodulatory effects in vitro. Viability of a probiotic is an important factor in virus infection. The probiotic L. rhamnosus GG reduced days with respiratory tract symptoms. In children, L. rhamnosus GG alone was not effective in reducing viral occurrence in the nasopharynx. However in otitis-prone children, L. rhamnosus GG in a combination reduced the numbers of human bocavirus.
  • Hatakka, Katja (Helsingin yliopisto, 2007)
    Infectious diseases put an enormous burden on both children and the elderly in the forms of respiratory, gastrointestinal and oral infections. There is evidence suggesting that specific probiotics may be antagonistic to pathogens and may enhance the immune system, but the clinical evidence is still too sparce to make general conclusions on the disease-preventive effects of probiotics. This thesis, consisting of four independent, double-blind, placebo-controlled clinical trials, investigated whether Lactobacillus GG (LGG) or a specific probiotic combination containing LGG would reduce the risk of common infections or the prevalence of pathogens in healthy and infection-prone children and in independent and institutionalised elderly people. In healthy day-care children, the 7-month consumption of probiotic milk containing Lactobacillus GG appeared to postpone the first acute respiratory infection (ARI) by one week (p=0.03, adjusted p=0.16), and to reduce complicated infections (39% vs. 47%, p<0.05, adjusted p=0.13), as well as the need for antibiotic treatment (44% vs. 54%, p=0.03, adjusted p=0.08) and day-care absences (4.9 vs. 5.8 days, p=0.03, adjusted p=0.09) compared to the placebo milk. In infection-prone children, the 6-month consumption of a combination of four probiotic bacteria (LGG, L. rhamnosus LC705, Propionibacterium freudenreichii JS, Bifidobacterium breve 99) taken in capsules appeared to reduce recurrent ARIs (72% vs. 82%, p<0.05; adjusted p=0.06), and the effect was particularly noticeable in a subgroup of children with allergic diseases (12% vs. 33%, p=0.03), although no effect on the presence of nasopharyngeal rhinovirus or enterovirus was seen. The 5-month consumption of the same probiotic combination did not show any beneficial effects on the respiratory infections in frail, institutionalised elderly subjects. In healthy children receiving Lactobacillus GG, the reduction in complications resulted in a marginal reduction in the occurrence of acute otitis media (AOM) (31% vs. 39%, p=0.08; adjusted p=0.19), and the postponement of the first AOM episode by 12 days (p=0.04; adjusted p=0.09). However, in otitis-prone children, a probiotic combination did not reduce the occurrence of AOM or the total prevalence of common AOM pathogens (Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis), except in the case of children with allergic diseases, in whom probiotics reduced recurrent AOM episodes (0% vs. 14%, p=0.03). In addition, interaction between probiotics and bacterial carriage was seen: probiot-ics reduced AOM in children who did not carry any bacterial pathogens (63% vs. 83%), but the effect was the reverse in children carrying bacteria in the nasopharynx (74% vs 62%) (p<0.05). Long-term probiotic treatment, either LGG given in milk to healthy children for 7 months or a combination of probiotics given in capsules to institutionalised elderly subjects for 5 months, did not reduce the occurrence of acute diarrhoea. However, when the probiotic combination (LGG, L. rhamnosus LC705, Propionibacterium JS) was given in cheese to independent elderly subjects for 4 months, the oral carriage of high Candida counts was reduced in the probiotic group vs. the placebo group (21% vs. 34%, p=0.01, adjusted p=0.004). The risk of hyposalivation was also reduced in the probiotic group (p=0.05). In conclusion, probiotics appear to slightly alleviate the severity of infections by postponing their appearance, by reducing complications and the need for antimicrobial treatments. In addition, they appear to prevent recurrent infections in certain subgroups of children, such as in infection-prone children with allergic diseases. Alleviating ARI by probiotics may lead to a marginal reduction in the occurrence of AOM in healthy children but not in infection-prone children with disturbed nasopharyngeal microbiota. On the basis of these results it could be supposed that Lactobacillus GG or a specific combination containing LGG are effective against viral but not against bacterial otitis, and the mechanism is probably mediated through the stimulation of the immune system. A specific probiotic combination does not reduce respiratory infections in frail elderly subjects. Acute diarrhoea, either in children or in the elderly, is not prevented by the continuous, long-term consumption of probiotics, but the consumption of a specific probiotic combination in a food matrix is beneficial to the oral health of the elderly, through the reduction of the carriage of Candida.
  • Ilveskero, Sorella (Helsingin yliopisto, 2005)
  • Uittamo, Johanna (Helsingin yliopisto, 2012)
    Oral cancer is the seventh most common cancer worldwide and its incidence is increasing. The most important risk factors for oral cancer are chronic alcohol consumption and tobacco smoking, up to 80 % of oral carcinomas are estimated to be caused by alcohol and tobacco. They both trigger an increased level of salivary acetaldehyde, during and after consumption, which is believed to lead to carcinogenesis. Acetaldehyde has multiple mutagenic features and it has recently been classified as a Group 1 carcinogen for humans by the International Agency for Research on Cancer. Acetaldehyde is metabolized from ethanol by microbes of oral microbiota. Some oral microbes possess alcohol dehydrogenase enzyme (ADH) activity, which is the main enzyme in acetaldehyde production. Many microbes are also capable of acetaldehyde production via alcohol fermentation from glucose. However, metabolism of ethanol into acetaldehyde leads to production of high levels of this carcinogen. Acetaldehyde is found in saliva during and after alcohol consumption. In fact, rather low ethanol concentrations (2-20mM) derived from blood to saliva are enough for microbial acetaldehyde production. The high acetaldehyde levels in saliva after alcohol challenge are explained by the lack of oral microbiota and mucosa to detoxify acetaldehyde by metabolizing it into acetate and acetyl coenzymeA. The aim of this thesis project was to specify the role of oral microbes in the in vitro production of acetaldehyde in the presence of ethanol. In addition, it was sought to establish whether microbial metabolism could also produce acetaldehyde from glucose. Furthermore, the potential of xylitol to inhibit ethanol metabolism and acetaldehyde production was explored. Isolates of oral microbes were used in the first three studies. Acetaldehyde production was analyzed after ethanol, glucose and fructose incubation with gas chromatography measurement. In studies I and III, the ADH enzyme activity of some microbes was measured by fluorescence. The effect of xylitol was analyzed by incubating microbes with ethanol and xylitol. The fourth study was made ex vivo and microbial samples obtained from different patient groups were analyzed. This work has demonstrated that isolates of oral microbiota are able to produce acetaldehyde in the presence of clinically relevant ethanol and glucose concentrations. Significant differences were found between microbial species and isolates from different patient groups. In particular, the ability of candidal isolates from APECED patients to produce significantly more acetaldehyde in glucose incubation compared to healthy and cancer patient isolates is an interesting observation. Moreover, xylitol was found to reduce their acetaldehyde production significantly. Significant ADH enzyme activity was found in the analyzed high acetaldehyde producing streptococci and candida isolates. In addition, xylitol was found to reduce the ADH enzyme activity of C. albicans. Some results from the ex vivo study were controversial, since acetaldehyde production did not correlate as expected with the amount of microbes in the samples. Nevertheless, the samples isolated from patients did produce significant amounts of acetaldehyde with a clinically relevant ethanol concentration.
  • Siironen, Päivi (Helsingin yliopisto, 2005)