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  • Viskari-Lähdeoja, Suvi (Helsingin yliopisto, 2013)
    Background and aims. Sudden infant death syndrome (SIDS) is a rare lethal event occurring in 0.1 to 0.3 of infants. In Finland, 10 to 20 infants die from SIDS annually. Research has defined many risk factors for SIDS, but the cascade leading to death remains unexplained. Cardiovascular recordings of infants succumbing to SIDS, as well as animal models, suggest that the final sequelae involve cardiovascular collapse resembling hypotensive shock. There is also evidence of previous hypoxia in SIDS infants. In animal studies, vestibulo-mediated cardiovascular control has been shown to be important in hypotensive shock. Hence, we hypothetized that SIDS victims may have impaired vestibulo-mediated cardiovascular control, possibly due to previous hypoxic episodes. In this thesis, we studied cardiovascular control, and especially vestibulo-mediated cardiovascular control in infants with known risk factors for SIDS at 2 to 4 months of age when the risk for SIDS is highest. Study subjects. A full polysomnographic recording with continuous blood pressure (BP) measurement was performed in 50 infants at 2-4 months of age: 20 control infants, nine infants with univentricular heart (UVH) suffering from chronic hypoxia, 10 infants with bronchopulmonary dysplasia (BPD) with intermittent postnatal hypoxic events, and 11 infants whose mothers had smoked during pregnancy, and thus had been exposed to intrauterine hypoxia and nicotine, were studied. In addition, 20 preterm infants were studied at the gestational age of 34-39 weeks to evaluate developmental aspects of cardiovascular control during head-up tilt test and vestibular stimulus. Methods. Linear side motion and 45° head-up tilt tests were performed in quiet non-rapid eye movement sleep (NREM). Heart rate (HR) and BP responses were analysed from the tests without signs of subcortical or cortical arousal. In addition, HR variability during NREM sleep was assessed. As a general marker of cardiovascular reactivity, HR response to spontaneous arousal from NREM sleep was also evaluated. Results.Side motion test. In the side motion test, control infants presented a biphasic response. First, there was a transient increase in HR and BP. This was followed by a decrease in BP to below baseline, and a return to baseline in HR. All other infant groups showed altered responses. UVH infants and preterm infants near term age had markedly reduced responses. Infants with BPD presented with variable responses: some responded similarly to controls, whereas others showed no initial increase in BP, and the following BP decrease was more prominent. Infants with intrauterine exposure to cigarette smoke showed flat initial BP responses, and the following decrease was more prominent, similarly to a subgroup of BPD infants. Tilt test. Control infants presented with a large variability in BP responses to head-up tilting. On average, systolic BP remained, at first, close to baseline, and diastolic BP increased, after which both decreased and remained below baseline even at the end of the tilt test. On average, HR showed a biphasic response with an initial increase followed by a decrease to below and, finally, a return to baseline. UVH infants showed a similar BP response, but their HR response was tachycardic. Preterm infants with BPD presented with an even greater variability in their BP responses to head-up tilts than control infants, but the overall response as a group did not differ from that of the controls. The tilt response of infants exposed to maternal cigarette smoking during pregnancy did not markedly differ from the control response. Preterm infants near term age showed attenuated responses in both cardiovascular measures, together with greater inter-subject variability compared to the control infants. Discussion. In conclusion, the studied infants with SIDS risk factors showed altered vestibulo-mediated cardiovascular control during the linear side motion test and head-up tilt test. The findings support our initial hypothesis that some infants with SIDS risk factors have defective vestibulo-mediated cardiovascular control, which may lead to death in life-threatening situations.
  • Kalliokoski, Annikka (Helsingin yliopisto, 2008)
    Organic anion-transporting polypeptide 1B1 (OATP1B1), encoded by the SLCO1B1 gene, is an influx transporter expressed on the sinusoidal membrane of human hepatocytes. The common c.521T>C (p.Val174Ala) single-nucleotide polymorphism (SNP) of the SLCO1B1 gene has been associated with reduced OATP1B1 transport activity in vitro and increased plasma concentrations of several of its substrate drugs in vivo in humans. Another common SNP of the SLCO1B1 gene, c.388A>G (p.Asn130Asp), defining the SLCO1B1*1B (c.388G-c.521T) haplotype, has been associated with increased OATP1B1 transport activity in vitro. The aim of this thesis was to investigate the role of SLCO1B1 polymorphism in the pharmacokinetics of the oral antidiabetic drugs repaglinide, nateglinide, rosiglitazone, and pioglitazone. Furthermore, the effect of the SLCO1B1 c.521T>C SNP on the extent of interaction between gemfibrozil and repaglinide as well as the role of the SLCO1B1 c.521T>C SNP in the potential interaction between atorvastatin and repaglinide were evaluated. Five crossover studies with 2-4 phases were carried out, with 20-32 healthy volunteers in each study. The effects of the SLCO1B1 c.521T>C SNP on single doses of repaglinide, nateglinide, rosiglitazone, and pioglitazone were investigated in Studies I and V. In Study II, the effects of the c.521T>C SNP on repaglinide pharmacokinetics were investigated in a dose-escalation study, with repaglinide doses ranging from 0.25 to 2 mg. The effects of the SLCO1B1*1B/*1B genotype on repaglinide and nateglinide pharmacokinetics were investigated in Study III. In Study IV, the interactions of gemfibrozil and atorvastatin with repaglinide were evaluated in relation to the c.521T>C SNP. Plasma samples were collected for drug concentration determinations. The pharmacodynamics of repaglinide and nateglinide was assessed by measuring blood glucose concentrations. The mean area under the plasma repaglinide concentration-time curve (AUC) was ~70% larger in SLCO1B1 c.521CC participants than in c.521TT participants (P ≤ 0.001), but no differences existed in the pharmacokinetics of nateglinide, rosiglitazone, and pioglitazone between the two genotype groups. In the dose-escalation study, the AUC of repaglinide was 60-110% (P ≤ 0.001) larger in c.521CC participants than in c.521TT participants after different repaglinide doses. Moreover, the AUC of repaglinide increased linearly with repaglinide dose in both genotype groups (r > 0.88, P 0.001). The AUC of repaglinide was ~30% lower in SLCO1B1*1B/*1B participants than in SLCO1B1*1A/*1A (c.388AA-c.521TT) participants (P = 0.007), but no differences existed in the AUC of nateglinide between the two genotype groups. In the drug-drug interaction study, the mean increase in the repaglinide AUC by gemfibrozil was ~50% (P = 0.002) larger in c.521CC participants than in c.521TT participants, but the relative (7-8-fold) increases in the repaglinide AUC did not differ significantly between the genotype groups. In c.521TT participants, atorvastatin increased repaglinide peak plasma concentration and AUC by ~40% (P = 0.001) and ~20% (P = 0.033), respectively. In each study, after repaglinide administration, there was a tendency towards lower blood glucose concentrations in c.521CC participants than in c.521TT participants. In conclusion, the SLCO1B1 c.521CC genotype is associated with increased and the SLCO1B1*1B/*1B genotype with decreased plasma concentrations of repaglinide, consistent with reduced and enhanced hepatic uptake, respectively. Inhibition of OATP1B1 plays a limited role in the interaction between gemfibrozil and repaglinide. Atorvastatin slightly raises plasma repaglinide concentrations, probably by inhibiting OATP1B1. The findings on the effect of SLCO1B1 polymorphism on the pharmacokinetics of the drugs studied suggest that in vivo in humans OATP1B1 significantly contributes to the hepatic uptake of repaglinide, but not to that of nateglinide, rosiglitazone, or pioglitazone. SLCO1B1 polymorphism may be associated with clinically significant differences in blood glucose-lowering response to repaglinide, but probably has no effect on the response to nateglinide, rosiglitazone, or pioglitazone.
  • Porthan, Kimmo (Helsingin yliopisto, 2011)
    Electric activity of the heart consists of repeated cardiomyocyte depolarizations and repolarizations. Abnormalities in repolarization predispose to ventricular arrhythmias. In body surface electrocardiogram, ventricular repolarization generates the T wave. Several electrocardiographic measures have been developed both for clinical and research purposes to detect repolarization abnormalities. The study aim was to investigate modifiers of ventricular repolarization with the focus on the relationship of the left ventricular mass, antihypertensive drugs, and common gene variants, to electrocardiographic repolarization parameters. The prognostic value of repolarization parameters was also assessed. The study subjects originated from a population of more than 200 middle-aged hypertensive men attending the GENRES hypertension study, and from an epidemiological survey, the Health 2000 Study, including more than 6000 participants. Ventricular repolarization was analysed from digital standard 12-lead resting electrocardiograms with two QT-interval based repolarization parameters (QT interval, T-wave peak to T-wave end interval) and with a set of four T-wave morphology parameters. The results showed that in hypertensive men, a linear change in repolarization parameters is present even in the normal range of left ventricular mass, and that even mild left ventricular hypertrophy is associated with potentially adverse electrocardiographic repolarization changes. In addition, treatments with losartan, bisoprolol, amlodipine, and hydrochlorothiazide have divergent short-term effects on repolarization parameters in hypertensive men. Analyses of the general population sample showed that single nucleotide polymorphisms in KCNH2, KCNE1, and NOS1AP genes are associated with changes in QT-interval based repolarization parameters but not consistently with T-wave morphology parameters. T-wave morphology parameters, but not QT interval or T-wave peak to T-wave end interval, provided independent prognostic information on mortality. The prognostic value was specifically related to cardiovascular mortality. The results indicate that, in hypertension, altered ventricular repolarization is already present in mild left ventricular mass increase, and that commonly used antihypertensive drugs may relatively rapidly and treatment-specifically modify electrocardiographic repolarization parameters. Common variants in cardiac ion channel genes and NOS1AP gene may also modify repolarization-related arrhythmia vulnerability. In the general population, T-wave morphology parameters may be useful in the risk assessment of cardiovascular mortality.
  • Vesterinen, Paula (Helsingin yliopisto, 2007)
    The aim of the studies was to improve the diagnostic capability of electrocardiography (ECG) in detecting myocardial ischemic injury with a future goal of an automatic screening and monitoring method for ischemic heart disease. The method of choice was body surface potential mapping (BSPM), containing numerous leads, with intention to find the optimal recording sites and optimal ECG variables for ischemia and myocardial infarction (MI) diagnostics. The studies included 144 patients with prior MI, 79 patients with evolving ischemia, 42 patients with left ventricular hypertrophy (LVH), and 84 healthy controls. Study I examined the depolarization wave in prior MI with respect to MI location. Studies II-V examined the depolarization and repolarization waves in prior MI detection with respect to the Minnesota code, Q-wave status, and study V also with respect to MI location. In study VI the depolarization and repolarization variables were examined in 79 patients in the face of evolving myocardial ischemia and ischemic injury. When analyzed from a single lead at any recording site the results revealed superiority of the repolarization variables over the depolarization variables and over the conventional 12-lead ECG methods, both in the detection of prior MI and evolving ischemic injury. The QT integral, covering both depolarization and repolarization, appeared indifferent to the Q-wave status, the time elapsed from MI, or the MI or ischemia location. In the face of evolving ischemic injury the performance of the QT integral was not hampered even by underlying LVH. The examined depolarization and repolarization variables were effective when recorded in a single site, in contrast to the conventional 12-lead ECG criteria. The inverse spatial correlation of the depolarization and depolarization waves in myocardial ischemia and injury could be reduced into the QT integral variable recorded in a single site on the left flank. In conclusion, the QT integral variable, detectable in a single lead, with optimal recording site on the left flank, was able to detect prior MI and evolving ischemic injury more effectively than the conventional ECG markers. The QT integral, in a single-lead or a small number of leads, offers potential for automated screening of ischemic heart disease, acute ischemia monitoring and therapeutic decision-guiding as well as risk stratification.
  • Gross, Andres (Helsingin yliopisto, 2007)
    This work studies the effect of clozapine (CLO) on the electroencephalography (EEG) and reactive oxygen species (ROS) production by peripheral blood monocytes (MO) in patients with schizophrenia (SCH). The aim of the study was to investigate the mechanism of action of CLO, to clarify the effect of CLO on EEG absolute power spectrum and ROS production, and explore the relationship of these effects with clinical response. We also tried to clarify whether the EEG changes or ROS production would help to identify the patients who were most likely to respond to treatment with CLO. Our findings suggest that the amount of slow background activity, particularly the absolute power of the theta frequency band, in the EEG is markedly increased by CLO treatment and this finding correlates positively with clinical improvement in patients with SCH. CLO affected the production of ROS by blood MO with reduction or minimal increase of the ROS production being associated with clinical improvement, whereas marked increase of the ROS production did not. Also a positive correlation between theta absolute power increase in the EEG and suppression of the production of ROS by blood MO was found. The correlations between different symptom clusters of SCH and the EEG rhythms were investigated; the absolute power of beta activity in the EEG seemed to correlate positively to overall psychopathology in patients with SCH showing inadequate response. The results suggest that the EEG background activity and investigation of the production of ROS by MO seem to be an adjunctive method to objectively assess and possibly predict the therapeutic effect of CLO in patients with chronic SCH showing inadequate response to treatment with conventional antipsychotics.
  • Oinonen, Annamari (Helsingin yliopisto, 2009)
    Chronic venous disease (CVD), including uncomplicated varicose veins and chronic venous insufficiency, is one of the most common medical conditions in the Western world. The central feature of CVD is venous reflux, which may be primary, congenital, or result from an antecedent event, usually an acute deep venous thrombosis (DVT). When the history of DVT is clear, the clinical manifestations of secondary CVD are commonly referred to as the post-thrombotic syndrome. Regardless of the underlying etiology, the final pathway leading to symptoms is ambulatory venous hypertension. The spectrum of symptoms and signs of CVD ranges from minor cosmetic problems to venous ulceration, which results in considerable morbidity and increased medical costs. Aims of this study were to evaluate the outcome of superficial venous surgery performed with or without preoperative duplex evaluation and venous marking with hand-held doppler, to assess short-term outcome of ultrasound-guided foam sclerotherapy in patients with axial superficial venous incompetence, as well as to compare reflux patterns after catheter-directed and systemic thrombolysis of deep ileofemoral venous thrombosis, and to evaluate the long-term outcome of deep venous reconstructions for severe chronic venous insufficiency. The study consists of five separate retrospective projects and includes 315 patients. Of this, 133 patients had undergone superficial venous surgery 2 to 5 years earlier according to preoperative duplex examination and venous marking, or according to clinical evaluation alone, or to a written plan without venous marking. A total of 112 patients had undergone ultrasound-guided foam sclerotherapy 5.5 to 16.5 months before. In addition, 32 patients had received either catheter-directed or systemic thrombolysis for DVT 2 to 3 years earlier, and 38 patients had undergone deep venous reconstructions 2 to 7 years earlier. In the present studies, some venous reflux was present postoperatively irrespective of the method of evaluation or ablation of the reflux. It seemed, however, that preoperative examination with duplex ultrasound and marking of reflux sites before the operation by the operating surgeon improves the outcome of superficial venous surgery. Ultrasound-guided foam sclerotherapy is effective in elimination of venous reflux in selected cases in short-term follow-up. Catheter-directed thrombolysis for deep iliofemoral venous thrombosis reduces later reflux and most probably the development of post-thrombotic syndrome as well. The outcome of deep venous reconstructions, especially for post-thrombotic deep venous incompetence, is poor. Thus, prevention of valvular damage by active treatment of deep venous thrombosis is important.
  • Hyrskyluoto, Alise (Helsingin yliopisto, 2014)
    Huntington s disease (HD) is a fatal neurodegenerative disease with progressive motor dysfunction, cognitive decline and psychiatric disturbances. HD is caused by a CAG repeat expansion in the huntingtin (IT15) gene, which encodes the huntingtin protein. Mutations in huntingtin cause accumulation of protein aggregates with subsequent cell death and loss of neurons in the striatum and cortex. The exact molecular mechanisms by which mutant huntingtin (mHTT) induces cell death are not completely understood. Huntingtin protein participates in many cellular functions such as protein trafficking, transcriptional regulation and apoptosis. Mutant protein is cleaved to form N-terminal fragments containing the first 100-150 residues including the polyglutamine repeats, which are thought to be the toxic species found in aggregates. Previous studies have shown that endoplasmic reticulum (ER) stress is involved in the early pathogenesis of HD. However, the precise mechanisms by which mHTT proteins cause ER stress are still unclear. The aim of this thesis was to elucidate the early pathological changes in HD. The specific goal was to study in more detail how ER stress, alterations in autophagy and ubiquitin proteasome system and oxidative stress trigger the disease and by which mechanisms. This thesis also aimed to identify novel therapeutic targets for early pathogenic changes in HD. The results showed that growth arrest and DNA damage inducible gene 34 (GADD34) plays an important role in cell protection and mediates cytoprotective autophagy via the mammalian target of rapamycin (mTOR) pathway in mHTT expressing cells. Modulation of GADD34 may thus prove useful in counteracting cell degeneration accompanying HD. Our results also showed that the sigma-1 receptor (Sig1R) agonist PRE084 increased levels of cellular antioxidants by affecting the NF-κB pathway that is reduced by expression of mHTT proteins. The Sig1R agonist increased cell survival and counteracted the deleterious effects caused by N-terminal mHTT proteins. Compounds that influence the Sig1R may have beneficial effects in models of HD, which warrants further studies. This thesis also shows that overexpression of ubiquitin-specific protease-14 (Usp14) reduces cellular aggregates in mHTT expressing cells mainly via the ubiquitin proteasome system. Overexpression of Usp14 was able to inhibit phosphorylation of inositol requiring enzyme 1 (IRE1) in mHTT expressing cells and to protect against cell degeneration and caspase-3 activation. These results show ER stress induced IRE1 activation is part of mHTT toxicity, which is inhibited by Usp14.
  • Keränen, Ilona (Helsingin yliopisto, 2013)
    Gastric outlet obstruction (GOO) is a preterminal event in incurable malignancies of the gastrointestinal tract. Pancreatic cancer and gastric cancer are the most common causes for GOO. Colorectal cancer (CRC) is the most common etiology for colorectal obstruction (CRO). Other causes for CRO include extracolonic malignancies (ECM) and benign causes. Traditional treatment of GOO and CRO is surgery, but it carries a high rate of complications. Self-expanding metal stents (SEMS) have become an alternative for surgery in GOO and CRO. The aim of this work was to evaluate the results of endoscopic stenting (ES) in GOO and CRO. The study material consisted of 323 patients with GOO or CRO treated at Meilahti Hospital between January 1998 and December 2010. In study I, 104 patients with incurable GOO were included in the analysis. The study II population consisted of 97 patients with advanced gastric cancer and GOO, and of these 50 underwent ES, 26 palliative resection (PR), and 21 gastrojejunostomy (GJ). In study III, 21 patients with benign CRO were included in the analysis. The study IV population comprised 101 patients with malignant CRO, and of these 11 were stented as a bridge to surgery. In study IV, 66 underwent palliative stenting due to CRC and 24 due to ECM. In study I, a median GOOSS (gastric outlet scoring system) improved significantly from 0 to 2 after stenting, and 73% of the patients managed with one stenting procedure until death. In study II, ES resulted in a more rapid improvement in oral intake and a shorter hospital stay than GJ or PR. Complication rates were similar between the groups. In the PR group, symptom-free and overall survivals were longest. In multivariate survival analysis, independent prognostic factors were age, BMI, pre-procedure GOOSS, PR as treatment modality, and chemotherapy. In study III, 63% of anastomotic strictures (AS) were resolved with SEMS. Of diverticular strictures (DS), 30% were resolved with SEMS. Complication rate was 43%. Of the complications, 67% occurred for patients with DS or Crohn`s disease strictures. In study IV, a primary anastomosis rate in elective operations was 90% in the bridge to surgery group. In palliative stenting, clinical success rates were significantly lower for patients with ECM than for patients with CRC (63% vs. 94%, p<0.001). Between palliation groups, complication, operation, and stoma rates were similar. SEMS provides good palliation for patients with incurable GOO. In advanced gastric cancer and GOO, SEMS is a treatment of choice for patients unfit for surgery. PR seems to provide survival benefit, and should be considered as a treatment option for patients fit for surgery. In benign CRO, SEMS is a good treatment option in AS for selected patients. In DS and Crohn`s disease strictures, a high rate of complications limit the utility of SEMS. In malignant CRO, SEMS can be used as a bridge to surgery and as palliation. A higher clinical failure rate is associated with palliative stenting for ECM than for CRC.
  • Pitkäjärvi, Mari-Anne (Helsingin yliopisto, 2012)
    The purpose of this study was to obtain information to support decision making in the development of successful teaching strategies and clinical placements among English-Language-Taught Degree Programmes (ELTDP) in faculties of healthcare in Finnish universities of applied sciences. This was achieved by descriptions and analysis of the experiences and conceptions of students and teachers. A methodological triangulation was used to conduct the study. In the first phase, descriptions of the students and the teachers experiences of teaching strategies and clinical placements were sought. Data were collected from general nursing and public health nursing teachers (n=18) and also from nursing students (n=27) through focus groups interview. The data were analyzed through thematic content analysis. In the second phase, a structured questionnaire based on the results of the first phase and relevant literature was developed to further investigate the students views. This instrument included items grouped as dimensions for teaching strategies (7 dimensions) and for clinical placements (5 dimensions). The quantitative data were collected from 283 general nursing, public health nursing and physiotherapy students. Statistical methods were used to analyze the data, which compared Finnish students experiences with Finnish students experiences. The findings of the first phase of the study suggest that both students and teachers alike perceived concreteness of instruction as important for ELTDP students learning. Similarly, both groups emphasized the value of the use of a variety of student centered methods to promote the learning of everyone in the culturally diverse student population. The clinical placements were perceived as challenging, due to international students lack of Finnish or Swedish speaking proficiency and also due to their negative experiences in the placements. The findings of the second phase revealed that all ELTDP students experiences of the dimensions of teaching strategies were mainly positive. The most positive experiences for all were with the cultural diversity in the learning community and with concreteness and practicality of theoretical instruction. The most negative experiences were about assessments. The international students felt less satisfied with their lives than did their Finnish peers. However, all students felt motivated to complete their studies. Despite the fact that the international students felt welcome on their placements, they were more likely than the Finnish students to have had the experience of an unsupportive clinical environment. Key words: cultural diversity, healthcare student, teaching strategies, clinical placements, ELTDP students, conceptions of students and teachers.
  • Ning, Feng (Helsingin yliopisto, 2013)
    The objectives of this study were to investigate: 1) what the major risk factors are that have contributed to the rise in prevalence of type 2 diabetes in Chinese adults, and whether the joint effect of a family history of diabetes along with obesity on the risk of diabetes in the Chinese differs from that in the Finns; 2) the impact of the homeostasis model assessment of insulin resistance and beta cell function on glucose metabolism in relation to aging in people of Asian origin; 3) the relative risk for cardiovascular disease (CVD) mortality and morbidity associated with fasting plasma glucose (FPG) and 2-hour plasma glucose (2hPG) within the normoglycemic range in European populations. This study was based on datasets of the Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Asia (DECODA) and in Europe (DECODE) studies comprising 10307 men and 13429 women aged 30 to 74 years from 11 Asian cohorts, and 12566 men and 10874 women aged 25 to 90 years from 19 European cohorts. Type 2 diabetes and intermediate hyperglycemia in this study were determined by a 2-h 75g oral glucose tolerance test according to the World Health Organization/International Diabetes Federation criteria of 2006. The odds ratios for the prevalence of type 2 diabetes and intermediate hyperglycemia were estimated using logistic regression analysis. Cox proportional hazards analysis was performed to estimate the association between plasma glucose and CVD mortality and morbidity, adjusting for conventional cardiovascular risk factors. Between 2001 and 2006, the age-standardized prevalence of type 2 diabetes increased from 5.2% to 14.2% in men and from 7.2% to 14.5% in women in rural areas, from 12.6% to 19.4% in men and from 10.2% to 16.6% in women in urban areas in Qingdao, China. Age, family history of diabetes and waist circumference was independent risk factors for diabetes in both sexes and in both urban and rural areas (P less than 0.01 for all). A high level of education and a high income were inversely associated with the increased prevalence in all populations except in rural men (P less than 0.05). Obesity and a family history of diabetes were major risk factors for type 2 diabetes in men and women from China and Finland. Their synergetic effect on type 2 diabetes was significant in Finnish men, but not in Finnish women or the Chinese. The prevalence of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) increased with age in populations of Asian origin except IFG in the Indians living in India and in African men living in Mauritius. The age-related increase was more prominent for IGT than for IFG in both men and women. Adjustment for insulin resistance and beta cell function reduced the differences among age groups for all ethnic groups, but the risk gradient between age groups still remained significant for IGT. Within normoglycemic range, individuals whose baseline 2hPG did not return to FPG levels (Group II, 2hPG > FPG) were older and had higher baseline body mass index (BMI), blood pressure and fasting insulin levels compared with those whose baseline 2hPG did (Group I, 2hPG ≤ FPG) in Europeans. Hazard ratios (95% confidence intervals) for CVD mortality were 1.22 (1.05-1.41) in men, and 1.40 (1.03-1.89) in women for Group II versus Group I, adjusting for age, study cohort, BMI, FPG, total serum cholesterol, smoking status and hypertension status. The corresponding hazard ratios for the incidence of coronary heart disease, ischemic stroke and composite CVD events were 1.13 (0.93-1.37), 1.40 (1.06-1.85) and 1.20 (1.01-1.42) in men, and 1.33 (0.83-2.13), 0.94 (0.59-1.51) and 1.11 (0.79-1.54) in women, respectively. The increasing trends for CVD mortality and morbidity did not change substantially after additional adjustment for fasting insulin concentrations. In conclusion, this study confirmed the impact of established risk factors of age, obesity and a family history of diabetes on the risk of diabetes among the Chinese, which is consistent with literature, but the interaction between the risk factors might be different between ethnicities and requires further investigation. This study also disclosed the deleterious effect of high normal 2hPG levels on CVD mortality and morbidity, which has not been widely investigated previously. The findings further support the view that the CVD risk extends well below the diabetes diagnostic value based on the post-challenge glucose levels, and may have certain clinical implications regarding diabetes diagnosis and glycemic management targets.
  • Kolehmainen, Pekka (Helsingin yliopisto, 2014)
    Human parechovirus (HPeV) and Ljungan virus (LV) are non-enveloped, single-stranded RNA viruses that form the genus Parechovirus in the family Picornaviridae. The interest in these viruses has notably increased over the past 15 years because of their strengthened associations to human and animal diseases. HPeV types 1 and 3 have been associated with more severe infections in young children, such as infections of the central nervous system (CNS) and sepsis-like disease. Rodent-infecting LV has been suggested to possess zoonotic potential and induce various human diseases. However, the proof for this remains lacking. This study aimed to describe the epidemiological features of HPeVs in Finland and in the Netherlands, to examine the connection between HPeV-induced infection and human diseases and to study the circulation of LV in Finland. The epidemiological analysis of stool samples, collected from 1996 to 2007, revealed that HPeVs are highly common in healthy Finnish children. HPeV was primarily detectable in children under 2 years of age. Altogether, 39% of the study participants tested positive for HPeV at least once during the study period. HPeVs circulated throughout the year, with a distinct seasonal peak in October-November. The results indicated that not only the previously described HPeV1 but also HPeV genotypes 3 and 6 circulate in Finland. Microneutralisation assays, which were set up to detect HPeV1 to 6, the most common genotypes in Europe, provided a deeper understanding of HPeV seroprevalence in the Finnish and Dutch populations. Seropositivity for HPeV1, 2 and HPeV4 to 6 was high and moderate in adults, in contrast to seropositivity for HPeV3, which was extremely low. The serological data demonstrate that HPeV types 1 to 6 might be even more prevalent than previously assumed. All six HPeV types circulate in Finland. In addition to HPeV detection in background populations, we presented the first cases of severe infection in neonates with HPeV4 and, subsequently, the first isolation of this genotype in Finland. Five hospitalised neonates with a sepsis-like disease in the fall of 2012 were positive for HPeV. Four of these children had HPeV4, indicating a potential small epidemic of this genotype, whereas one HPeV remained untyped. In addition, we detected HPeV3 in a neonate with suspected viral sepsis in October 2011 and another untyped HPeV in a child with symptoms corresponding to acute disseminated encephalomyelitis in May 2012. Following these findings, we promoted the addition of HPeV detection to routine diagnostics of young children. To extend the knowledge regarding other parechoviruses in Finland, we studied LV antibody prevalence in both humans and rodents. The seroprevalence detected for LV was 38% in humans and 18% in bank voles (Myodes glareolus). The observation of LV antibodies in humans is relatively high because LV has never been isolated from humans. These results suggest that an LV or LV-like virus, in addition to HPeVs, circulates frequently among human populations in Finland.
  • Rautiainen, Henna (Helsingin yliopisto, 2008)
    Primary biliary cirrhosis (PBC) is caused by an autoimmune inflammation of the small bile ducts. It results to destruction of bile ducts, accumulation of the bile in the liver, and cirrhosis. The prevalence and incidence of PBC is increasing in the Western world. The prevalence is highest in the USA (402 per million) and incidence in Scotland (49/million/year). Our aim was to assess the epidemiology of PBC in Finland. Patients for the epidemiological study were searched from the hospital discharge records from year 1988 to 1999.The prevalence rose from 103 to 180/million from 1988 to 1999, an annual increase of 5.1%. The incidence rose from 12 to 17 /million/year, an annual increase of 3.5%. The age at death increased markedly from 65 to 76 years. The risk of liver related deaths diminished over time. The treatment of PBC is based on Ursodeoxycholic acid (UDCA). During 20 years 50% of patients end up with cirrhosis. Our treatment option was to combine budesonide, a potent corticosteroid with a high first pass metabolism in the liver, to UDCA and evaluate the liver effects and systemic effects such as bone mass density (BMD) changes. Our aim was to find out if combination of laboratory tests would serve as a surrogate marker for PBC and help reducing the need for liver biopsy. Non-cirrhotic PBC patients were randomized to receive budesonide 6 mg/day combined to UDCA 15 mg /kg/day or UDCA alone for three years. The combination therapy with UDCA and budesonide was effective: stage improved 22%, fibrosis 25%, and inflammation 32%. In the UDCA group the changes were: 20% deterioriation in stage and 70% in fibrosis, but a 10% improvement in inflammation. BMD in femoral neck decreased by 3.6% in the combination group and by 1.9% in the UDCA group. The reductions in lumbar spine were 2.8% and 0.7%. Pharmacokinetics did not differ between the stages of PBC. HA, PIIINP, bile acids, and AST were significantly different within stages I-III and could differentiate the mild fibrosis (F0F1) from the moderate (F2F3). The combination of these individual markers (PBC-score) further improved the accuracy. The area under the ROC of the PBC score, using a cut of value 66, had a sensitivity of 81.4% and a specificity of 65.2% to classify the stage of PBC. The prevalence of PBC in Finland increases, which results from increasing incidence and improved survival. The combination of budesonide and UDCA improves liver histology compared to UDCA alone in non-cirrhotic stages of PBC. The treatment may reduce BMD. Hyaluronic acid, PIIINP, AST, and bile acids may serve as tools to monitor the treatment response in the early stages of PBC. The budesonide and UDCA combination therapy is an option for those patients who do not receive full response from UDCA and are still at the non-cirrhotic stage of PBC.
  • Palo, Riikka (Helsingin yliopisto, 2013)
    Previously reported differences in transfusion practices suggest that transfusion protocols and clinical transfusion decisions may often be inappropriate. To change and monitor practices requires a follow-up system. A healthcare-integrated data-gathering system could provide the required information about blood use. The purpose of this observational study was to create a follow-up system for blood use and to gather information about transfused patients and transfusion practices in Finland. Data came from ten Finnish hospital districts (five university and five tertiary-care hospital districts) between the years 2002 and 2005. The collection process involved combining data from pre-existing electronic medical records applied for different purposes. This information was combined from these electronic systems by use of personal identification numbers and data expressed as hospital episodes. Variation in blood-use practices still existed between hospitals. For example, the percentage of red blood cell (RBC) receivers ranged in Finnish hospitals from 12% to 57% during primary knee-arthroplasty surgery. The most typical blood-transfused patient was an over 65-year-old woman receiving 2 units of RBCs. RBC products were usually transfused in pairs (such as in two-four-six units). In over 30% of FFP transfusions, plasma was given without any guidance from coagulation tests. Among moderately anemic parturients, transfusion of 0 to 2 units of RBC had no effect on length of hospitalization. Duration of hospitalization was, however, considerably longer in these anemic patients than for average Finnish mothers (5.2 days versus 3.5 days). Most of the platelet (PLT) products were transfused to hematological patients (43%). Only 1% of surgical patients received PLTs. Severity of underlying condition in surgical patients had an effect on prevalence of blood transfusions. Variability in blood-use practices suggests inappropriate blood use. Moreover, RBC transfusion in paired units is a questionable practice. FFP transfusions, not based on coagulation tests, suggest inappropriate use of plasma as well. In parturients, mild anemia treated with 1 to 2 units of RBCs does not shorten hospitalization time. This supports the current recommended thresholds for RBC transfusion. Improvement efforts concerning PLT-use practices may be directed to users of high doses of PLTs; to hematological patients, but also to digestive tract surgery and cardiac surgery patients. Knowledge of severity of the underlying disease as affecting the transfusion requirement may facilitate optimization of blood use.
  • Poikonen, Eira (Helsingin yliopisto, 2011)
    Candida species are an important cause of nosocomial bloodstream infections in hospitalized patients worldwide, with associated high mortality, excess length of stay and costs. Main contributors to candidemias is profound immunosuppression due to serious underlying condition or intensive treatments leading to an increasing number of susceptible patients. The rank order of causative Candida species varies over time and in different geographic locations. The aim of this study was to obtain information on epidemiology of candidemia in Finland, to identify trends in incidence, causative species, and patient populations at risk. In order to reveal possible outbreaks and assess the value of one molecular typing method, restriction enzyme analysis (REA), in epidemiological study, we analyzed C. albicans bloodstream isolates in Uusimaa region in Southern Finland during eight years. The data from the National Infectious Disease Register were used to assess the incidence and epidemiological features of candidemia cases. In Helsinki University Central Hospital (HUCH) all patients with blood culture yielding any Candida spp. were identified from laboratory log-books and from Finnish Hospital Infection Program. All the patients with a stored blood culture isolate of C. albicans were identified through microbiology laboratory logbooks, and stored isolates were genotyped with REA in the National Institute for Health and Welfare (former KTL). The incidence of candidemia in Finland is globally relatively low, but increased between between 1990s and 2000s. The incidence was highest in males >65 years of age, but incidence rates for patients <1-15 years were lower during 2000s than during 1990s. In HUCH the incidence of candidemia remained low and constant during our 18 years of observation, but a significant shift in patient-populations at risk was observed, associated with patients treated in intensive care units, such as premature neonates and surgical patients. The predominating causative species in Finland and in HUCH is C. albicans, but the proportion of C. glabrata increased considerably. The crude one-month case fatality was constantly high between 28-33%. REA differentiated efficiently between C. albicans blood culture isolates and no clusters were observed in the hospitals involved, despite of abundant transfer of patients among them. Candida spp. are an important cause of nosocomial blood stream infections in Finland, and continued surveillance is necessary to determine the overall trends and patient groups at risk, and reduce the impact of these infections in the future. Molecular methods provide an efficient tool for investigation of suspected outbreak and should be available in the future in Finland, also.
  • Kerola, Anne (Helsingin yliopisto, 2015)
    Rheumatoid arthritis (RA) is associated with a substantially increased risk for cardiovascular (CV) morbidity and mortality. Along with their CV burden, RA patients are at increased risk for other comorbidities such as hypothyroidism and depressive symptoms. The aim of this work was to evaluate the prevalence of CV comorbidities and hypothyroidism among RA patients in comparison to those of the general population at the time of RA diagnosis. We also aimed to determine, among patients with early RA, the contribution of psychiatric and CV comorbidities as causes of long-term work disability (WD). Lastly, we assessed CV mortality rates in early RA. Between 2000 and 2007, all patients diagnosed with RA in Finland were possible to identify from a Finnish nationwide register on special reimbursements for medicine expenses. The same register provided information on the presence of comorbidities antedating RA diagnosis. From the pension registers, we retrieved data on permanent or temporary disability pensions. Causes of death were obtainable until the end of 2008. We compared the main outcomes, that is, the prevalence of comorbidities at RA diagnosis, the incidence of comorbidity-related disability pensions, and CV mortality rates to those of the age- and sex-specific Finnish population, and calculated standardized rate, incidence and mortality ratios (SRRs, SIRs, and SMRs). In a population of 7,209 RA patients, the risk of having coronary heart disease (CHD) at RA diagnosis was slightly elevated, the SRR (95% CI) being 1.10 (1.01 1.20). The SRR for levothyroxine-treated hypothyroidism at RA diagnosis was 1.51 (1.35 to 1.67). SRR was highest, almost 2.5, among women with RA aged 20 to 49, the excess prevalence of hypothyroidism decreasing steadily and fading in older age groups. From 2000 to 2008, of 7,831 RA patients, 1,095 were granted a disability pension. The 9-year cumulative incidence of WD resulting from RA was 11.9%, from a psychiatric comorbidity 1.3%, and from a CV disease 0.5%. SIR of WD resulting from CV disease was 1.75 (1.23 to 2.51) and SIR of WD resulting from psychiatric disorders was 0.99 (0.80 to 1.23). By the end of 2008, of 14,878 RA patients, 1,157 had died, 501 (43%) from CV causes. The SMR in the entire RA cohort was 0.57 (0.52 0.62). To conclude, the risks for CHD and hypothyroidism were already higher among RA patients at RA diagnosis, highlighting the importance of CV risk detection and management and of vigilance for hypothyroidism. Psychiatric and CV comorbidities were the primary causes of long-term WD much less frequently than was RA itself; the risk for WD due to CV disease, however, was higher in RA than in the general population. During the era of modern treatment regimens for RA, the risk of CV death during the early years of RA was not elevated. All these findings together stress the importance of recognizing, preventing, and targeting comorbidities in RA, already in the early years of the disease.