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  • Putaala, Jukka (Helsingin yliopisto, 2010)
    Stroke is the second leading cause of death and the leading cause of disability worldwide. Of all strokes, up to 80% to 85% are ischemic, and of these, less than 10% occur in young individuals. Stroke in young adults—most often defined as stroke occurring under the age of 45 or 50—can be particularly devastating due to long expected life-span ahead and marked socio-economic consequences. Current basic knowledge on ischemic stroke in this age group originates mostly from rather small and imprecise patient series. Regarding emergency treatment, systematic data on use of intravenous thrombolysis are absent. For this Thesis project, we collected detailed clinical and radiological data on all consecutive patients aged 15 to 49 with first-ever ischemic stroke between 1994 and 2007 treated at the Helsinki University Central Hospital. The aims of the study were to define demographic characteristics, risk factors, imaging features, etiology, and long-term mortality and its predictors in this patient population. We additionally sought to investigate, whether intravenous thrombolysis is safe and beneficial for the treatment of acute ischemic stroke in the young. Of our 1008 patients, most were males (ratio 1.7:1), who clearly outnumbered females after the age of 44, but females were preponderant among those aged <30. Occurrence increased exponentially. The most frequent risk factors were dyslipidemia (60%), smoking (44%), and hypertension (39%). Risk factors accumulated in males and along aging. Cardioembolism (20%) and cervicocerebral artery dissection (15%) were the most frequent etiologic subgroups, followed by small-vessel disease (14%), and large-artery atherosclerosis (8%). A total of 33% had undetermined etiology. Left hemisphere strokes were more common in general. Posterior circulation infarcts were more common among those aged <45. Multiple brain infarcts were present in 23% of our patients, 13% had silent infarcts, and 5% had leukoaraiosis. Of those with silent brain infarcts, majority (54%) had only a single lesion, and most of the silent strokes were located in basal ganglia (39%) and subcortical regions (21%). In a logistic regression analysis, type 1 diabetes mellitus in particular predicted the presence of both silent brain infarcts (odds ratio 5.78, 95% confidence interval 2.37-14.10) and leukoaraiosis (9.75; 3.39-28.04). We identified 48 young patients with hemispheric ischemic stroke treated with intravenous tissue plasminogen activator, alteplase. For comparisons, we searched 96 untreated control patients matched by age, gender, and admission stroke severity, as well as 96 alteplase-treated older controls aged 50 to 79 matched by gender and stroke severity. Alteplase-treated young patients recovered more often completely (27% versus 10%, P=0.010) or had only mild residual symptoms (40% versus 22%, P=0.025) compared to age-matched controls. None of the alteplase-treated young patients had symptomatic intracerebral hemorrhage or died within 3-month follow-up. Overall long-term mortality was low in our patient population. Cumulative mortality risks were 2.7% (95% confidence interval 1.5-3.9%) at 1 month, 4.7% (3.1-6.3%) at 1 year, and 10.7% (9.9-11.5%) at 5 years. Among the 30-day survivors who died during the 5-year follow-up, more than half died due to vascular causes. Malignancy, heart failure, heavy drinking, preceding infection, type 1 diabetes, increasing age, and large-artery atherosclerosis causing the index stroke independently predicted 5-year mortality when adjusted for age, gender, relevant risk factors, stroke severity, and etiologic subtype. In sum, young adults with ischemic stroke have distinct demographic patterns and they frequently harbor traditional vascular risk factors. Etiology in the young is extremely diverse, but in as many as one-third the exact cause remains unknown. Silent brain infarcts and leukoaraiosis are not uncommon brain imaging findings in these patients and should not be overlooked due to their potential prognostic relevance. Outcomes in young adults with hemispheric ischemic stroke can safely be improved with intravenous thrombolysis. Furthermore, despite their overall low risk of death after ischemic stroke, several easily recognizable factors—of which most are modifiable—predict higher mortality in the long term in young adults.
  • Luostarinen, Tapio (Helsingin yliopisto, 2015)
    Cervical cancer is the 4th most common cancer in women. In its carcinogenesis human papillomavirus (HPV) 16/18 are most important. HPV6/11 cause benign lesions. A small proportion of HPV infection(s) develop into cancer. Therefore, joint effects between HPVs and putative co-factors, Chlamydia trachomatis and smoking, are of interest but largely open. The aims of this work were to understand joint effects of infections with 1) HPV types, 2) HPVs and C. trachomatis, and 3) order of these infections in the carcinogenesis. For the 1st two aims, two case-control studies were nested within cohorts of Nordic biobanks. 1st linkage to cancer registers identified 182 cases of invasive cervical cancer (ICC, 148 squamous cell carcinomas, SCC) with prediagnostic sera until 1994. 2nd linkage with a longer follow-up until 2002 comprised 604 new ICC cases. Incidence density sampled controls were individually matched for age at serum sampling, sample storage time and region. For the 3rd aim, a case-control study in a serial setting was nested within a cohort of Swedish women participating in a cervical cancer screening programme in 1969-1995, and 118 ICCs with age and sampling-time-matched controls were identified. Finally, a case-cohort study in the Finnish Maternity Cohort was based on women with two pregnancies within 5 years. The women were followed on average for 4.8 years, from the 2nd pregnancy sample until the end of 2004. During follow-up, 490 women were diagnosed with cervical high-grade precancer. A comparison subcohort of 2796 women was randomly sampled from age and calendar time strata. IgG antibodies to HPV 6/11/16/18/31/33/45 capsids, and C. trachomatis were determined by ELISA. Serum cotinine, a marker for recent smoking, was measured by immunoassays. HPV and C. trachomatis DNA in smears and biopsy specimen were examined by PCR. HPV DNA-positive specimens were typed. Rate ratios were estimated by conditional logistic or proportional hazards regression. Misclassification of HPV serology was corrected for. In the 1st study, we found no excess risk of cervical carcinoma among women seropositive for both HPV16 and HPV6/11. In the 2nd study, there was excess risk, but the joint effect was again significantly smaller than the expected joint effects. Finally, if infection with HPV6 preceded infection with high-risk HPV31, there was no material excess risk of in situ cervical carcinoma. The smaller than expected joint effect between HPV types was probably due to a cell-mediated immune response to past, natural HPV6/11 infection, of which the serum antibodies were a surrogate. The risk of ICC was highly increased not only among women whose 1st smear was HPV DNA-positive but also among C. trachomatis DNA-positive women. The risk was even higher among HPV or C. trachomatis DNA positives both at the start and end of follow-up. The risk of in situ cervical carcinoma was highly increased among women whose HPV18/45 and C. trachomatis infections were virtually concomitant. The risk of SCC was increased related to C. trachomatis, after adjusting/stratifying for HPV. These results support early HPV vaccination in cervical cancer prevention. C. trachomatis should not be ignored in the preventive efforts against cervical cancer.
  • Saarinen, Riitta (Helsingin yliopisto, 2012)
    In parotitis, one or both of the parotid glands swell, causing pain while eating, reduced mouth opening, and in some cases fever. Before the vaccination era, mumps was the commonest cause of childhood parotitis. Nowadays acute pediatric parotitis is rare, and the causative agent(s) are not fully known. It is assumed that other viruses in addition to mumps virus are capable of causing similar symptoms. Some children develop recurrent symptoms i.e. juvenile recurrent parotitis (JRP). If symptoms are frequent, this condition can be quite life-disruptive. Fortunately, JRP often resolves in puberty. The etiology and pathophysiology of this juvenile recurrent parotid inflammation are other aspects currently not completely understood. The aim of the present study was to assess the epidemiology, etiology, clinical picture, and outcome for pediatric parotitis at present. In addition, it addresses differential diagnosis and complications. A group of 41 children aged ≤17 with acute parotid inflammation was collected prospectively for this study that reported clinical characteristics, treatment, outcome and complications. Another group of 133 children was collected retrospectively with the clinical picture of their disease reported, as well. The serine protease inhibitor Kazal-type 1 (SPINK-1) genotype was tested in 88 parotitis patients, since mutation of this gene disposes to pancreatitis, and salivary glands bear some resemblance to the pancreas in function. To map the etiology of parotitis, a questionnaire about history of parotitis, and parotid gland -related symptoms went to 1,000 adolescents randomly selected. In addition, human herpes viruses (HHVs) from saliva samples of children with acute parotid inflammation, and from healthy controls were tested. To assess the differential diagnosis and complications of parotitis, the database of Helsinki University Central Hospital, Department of Otorhinolaryngology - Head and Neck Surgery, was searched according to ICD-10 codes in order to find all children diagnosed and treated due to osteomyelitis or parotid abscess. All prospectively studied children with acute parotitis were in good general condition, and most episodes of parotitis in childhood seem to have a benign course. Half these children were treated only with non-steroidal anti-inflammatory drugs. However, parotid symptoms have a tendency to recur in about half the cases. About 1% of the respondents to the epidemiologic survey had suffered from parotitis. Heredity similar to pancreatitis could not be shown, since no difference emerged in SPINK-1 genotype in children with parotitis compared to controls. HHVs seem to play no role in acute juvenile parotitis, but are instead common findings in saliva. Osteomyelitis of the head and neck region is rare, but important in differential diagnosis of children with recurrent parotid symptoms. Parotitis-related complications are rare. Parotid abscesses are multi-bacterial infections with intravenous antibiotic therapy being the cornerstone of treatment. Surgical drainage assists in recovery and does not lead to fistula formation. In conclusion, according to this study juvenile parotitis has a frequency close to 1%, it has a tendency to recur, and in most cases the overall condition of the child is good during the infection. Osteomyelitis as a differential diagnosis must be kept in mind when treating recurrent symptoms of the parotid area. Abscesses related to parotitis are rare. The full etiology of juvenile parotitis still remains to be discovered.
  • Skyttä, Eerik (Helsingin yliopisto, 2006)
    Juvenile idiopathic arthritis (JIA) is associated with growth disturbances, especially leg length discrepancy (LLD) and knee valgus deformity (KVD). Studies have demonstrated growth plate stimulation with chronic arthritis. In the context of surgical treatment of LLD or KVD of a growing knee, the less invasive procedures, which allow immediate mobilisation, are preferred. Establishment of the skeletal age and the correction potential in the knees of rheumatic children is difficult due to rheumatic changes. In this present work, an analysis of the efficacy, safety and long-term results of temporary epiphyseal arrests performed in Rheumatism Foundation Hospital (Heinola, Finland). The distribution of diagnoses among children (n=71) with JIA and LLD (68 knees) was consistent with the normal oligoarthritis-predominated population of children with JIA. A higher male:female ratio (1:1.7 vs. 1:2.4 in population-based studies (PBS)) and earlier mean onset age (4 vs. 7 years in PBSs) were, however, distinct features in the study population. In most cases the correction was reliable and temporary arrest produced a mean correction of 1mm per month. The time of arrest required, however, varied significantly, probably due to the effect of underlying diseases and medication, and the age of the child. All complications encountered (10%) were minor. The correction achieved persisted in long-term follow-up. KVD (n=112, 177 knees) was associated with a high proportion of polyarthritic disease subtype (45% vs. 12-31% in PBSs), and the male:female distribution was grossly female-dominated (1:4.9 vs. 1:2.4 in PBSs). The early mean onset age (3 vs. 7 years in PBSs) was also notable in this cohort. Successful correction was achieved in 2/3 cases and the mean angular correction was 0.7 degrees per month. The required time of arrest, however, varied considerably. In 13% of knees the paucity of follow-up visits resulted in over-correction to varus. The complication rate (3%) in the knees operated for KVD was considerably lower compared to ten per cent in the management of LLD. Most of the complications related to epiphyseal stapling were reversible. However, the risk of premature closure of growth plates does exist. The number of over-corrections was notably high, with 13% knees turning to varus. The correction achieved persisted in long-term follow-up.
  • Laitinen, Eeva-Maria (Helsingin yliopisto, 2012)
    Congenital hypogonadotropic hypogonadism (HH) is a rare explanation for absent or delayed puberty. HH is caused by a lack or reduced number of gonadotropin-releasing hormone (GnRH) neurons, or disrupted secretion or action of GnRH. If HH appears with defects in sense of smell, the condition is termed Kallmann syndrome (KS). Clinical and genetic features of KS and congenital HH with normal sense of smell (normosmic HH; nHH) are heterogeneous, and the disease phenotype may even differ within the same family. Severity of HH may vary from cryptorchidism and micropenis in infant boys and absent pubertal development to reversal of HH later in life. This study aimed to characterize the clinical and genetic features of patients with KS or nHH, as well as the features of those who had recovered from HH later in life, and to estimate the frequency of KS in Finland. We also investigated the long-term associations of treatment of HH on bone health. In addition, we investigated the role of HH genes in the etiology of isolated cryptorchidism. Patients previously diagnosed with congenital HH were enrolled at all five university hospitals in Finland. Participants underwent detailed clinical examination and dual energy x-ray absorptiometry (DXA) scan for bone mineral density (BMD) assessment. Serum reproductive hormones and bone turnover markers were measured. In addition, recovery of HH was assessed after treatment withdrawal. Subjects with congenital HH (KS or nHH) were screened for mutation(s) in genes involved in development and/or migration of GnRH neurons: KAL1 (KS patients only), FGFR1, FGF8, PROK2, PROKR2, CHD7, and WDR11. Normosmic subjects were also screened for mutation(s) in the additional genes regulating secretion and/or action of GnRH: GNRHR, GNRH1, TAC3, TACR3, KISS1, and KISS1R. Furthermore, FGFR1, PROK2, PROKR2, GNRHR, TAC3, and TACR3 were screened in 54 boys and men from 46 families with isolated cryptorchidism, but no other features of HH. The minimal incidence estimate of KS in Finland between 1976 and 1987 was 1:48 000, with a clear difference between boys (1:30 000) and girls (1:125 000) (p=0.02). The reproductive phenotype of 35 KS patients (29 men) and 10 nHH patients (6 men) ranged from severe HH to reversal of HH later in life (n=6, all men). Twenty-six patients underwent DXA scan, and BMDs of all measured sites were lower in subjects who had had long (>5 years) treatment pauses or low-dose testosterone treatment (n=9) as compared to subjects without such a history (n=17; all p-values<0.05). Altogether, mutational analysis revealed mutation(s) in 19 of 45 index cases: three KS men had a mutation in KAL1, six women (5 KS and 1 nHH) and five KS men (one with reversal of HH) had an FGFR1 mutation, one KS man with HH reversal harbored a CHD7 mutation, and two normosmic men both with reversal, and one pair of sisters all had compound heterozygous mutations in GNRHR. No other mutations in screened genes were found. Two of the 46 index cases with isolated cryptorchidism were heterozygous carriers of a single GNRHR mutation, also present in male controls at a similar frequency (3/120; p=0.62). In conclusion, KS is a rare condition, with a minimal incidence estimate of 1:48 000 in Finland. Approximately 40% of the cases attained a molecular genetic cause for the condition; particularly, Finnish KS women frequently harbored a mutation in FGFR1. A considerable proportion of male patients with HH may recover in early adulthood. We therefore recommend that all adolescents and young adults with congenital HH should be informed on the possibility of reversal. However, HH patients may still require life-long follow-up to avoid inadequate hormone treatment, long treatment pauses, and further morbidity. Finally, isolated cryptorchidism is not commonly caused by defects in genes involved in congenital HH.
  • Ristola, Mervi (Helsingin yliopisto, 2012)
    Glomerular epithelial cells, podocytes, and the specialized cell junctions termed slit diaphragms (SDs) between interdigitating foot processes of the podocytes form the essential components of the filtration barrier in the kidney glomerulus. Nephrin is a transmembrane immunoglobulin superfamily member and a crucial structural and signalling component of the SD. Mutations in the nephrin gene cause congenital nephrotic syndrome of the Finnish type (CNF), leading to disruption of the SD and leakage of plasma proteins into the urine. The Neph-protein family comprises Neph1, Neph2 and Neph3; these are nephrin homologues and also important components of the SD. Interactions between nephrin and Neph1-3 are suggested to play a role in cell adhesion and thus serve as a structural framework of the SD. This thesis investigated the interactions and cell adhesion activities of nephrin and Neph-family members. Neph3 was shown to belong to the nephrin protein complex and to form homodimers. Both Neph1 and Neph3 were demonstrated to participate in the formation of cell-cell contacts by their homophilic interactions. Cell adhesion was also promoted by heterophilic trans-interactions between nephrin and Neph1 or Neph3. These adhesive activities may play an important role in the formation and function of the SD. In nephrin-deficient mice, where SDs are replaced by tight junction-like structures, Neph3 was shown to be up-regulated. This suggests that Neph3 may be involved in molecular mechanisms that are associated with morphological changes in injured podocytes. Nephrin and Neph3 genes, NPHS1 and KIRREL2, respectively, are located on human chromosome 19q13.12 in a head-to-head orientation separated by an approximately 5-kb intergenic region. A similar bidirectional arrangement of nephrin and Neph3 genes is present in mouse and rat chromosomes. The bidirectional and conserved arrangement of nephrin and Neph3 genes together with their similar protein structure and location suggest that nephrin and Neph3 genes may share key features in their regulation. This thesis focused on investigating transcriptional regulatory mechanisms important for nephrin and Neph3 genes. Transcription factors WT1 and NF-κB were shown to function co-operatively in both nephrin and Neph3 gene regulation. Further, DNA methylation participated in silencing both nephrin and Neph3 gene expression. These similar mechanisms in regulating transcription of nephrin and Neph3 genes may produce their similar spatial and temporal expression as well as similar function. In addition, transcription factors GABP and Sp1 were found to regulate nephrin and Neph3 genes, respectively. The results of this thesis widen the current understanding of the role of nephrin and Neph-family members in the formation of the SD; Neph3 belongs to the nephrin protein complex sharing similar binding properties with nephrin, Neph1 and Neph2, and interactions of nephrin, Neph1 and Neph3 promote cell adhesion. Further, nephrin and Neph3 genes were demonstrated to share similar transcriptional regulatory mechanisms. This may improve understanding of the transcriptional regulation of podocytes in general.
  • Kuure, Satu (Helsingin yliopisto, 2007)
    The permanent mammalian kidney (metanephros) develops as a result of complex reciprocal tissue interactions between a ureteric epithelium and the renal mesenchyme. The overall goal of the research in this thesis was to gain data that will eventually help in elucidating the formation of congenital renal malformations. The experiments in my thesis aimed to reveal the mechanisms by which Notch, Wnt and GDNF/Ret signalling pathways regulate the development of functional kidney. The function of Notch pathway was studied by a transgenic mouse model, where it was shown that overactivation of Notch signalling disturbs kidney development and alters the expression of Gdnf and Ret/GFRa1. This indicates that Notch signalling interplays with GDNF/Ret in the regulation of the primary ureteric budding and its subsequent branching. The data also suggested that strict spatio-temporal regulation of these two pathways is required for determination of ureteric tip-identity, which appeared to be crucial for the branch formation. The function of Wnt signalling in the ureteric morphogenesis was studied by in vivo and in vitro methods to show that a canonical pathway is required for ureteric branching. Stabilisation and deletion of the canonical pathway mediator, b-catenin specifically in the ureteric epithelium result in renal aplasia/hypodysplasia. These defects originate from severe blockage of ureteric branching due to the disrupted Ret signalling. Consequently, ureteric tip specific markers are lost and ureteric stalk identity is expanded throughout the whole epithelium. Thus, the data demonstrates that the Wnt/b-catenin pathway plays an essential role in the patterning and branching of the ureteric epithelium. A novel in vitro method was generated and utilised in nephron induction studies to reveal the mechanisms through which nephrogenesis is induced. Transient GSK3 inhibition results in stabilisation of b-catenin in the isolated renal mesenchyme, which efficiently triggers nephron formation. Also genetic stabilisation of b-catenin specifically in the mesenchyme results in spontaneous nephrogenesis. The results show that activation of the canonical Wnt pathway is sufficient to initiate nephrogenesis, and suggest that this pathway mediates the nephron induction in murine kidney mesenchymes. Taken together, this thesis demonstrates Notch and Wnt signalling pathways as novel regulators of ureteric branching morphogenesis, and that activation of the canonical Wnt pathway is sufficient for nephron induction. The studies also indicate that the Notch and Wnt pathways cross-talk with GDNF/Ret signalling in the patterning of ureteric epithelium.
  • Isoaho, Pia (Helsingin yliopisto, 2012)
    Specific language impairment (SLI) has an estimated prevalence between two and seven percent. SLI can effect production and/or understanding of speech. International longitudinal studies have shown SLI to be constant and to have strong influence on individuals life. At school age SLI is a risk factor for reading disabilities and broader learning disabilities. In Finland, the study of SLI is sparse. Thesis examines the development of linguistic abilities in SLI in school-aged children. It also focuses on the interplay between this development and reading and mathematical abilities. In the study, I observed the development of linguistic abilities of 43 children with a diagnosis of SLI at the age of 7 9 (1.-3. grades). Battery of tests was used yearly to map children s language abilities, reading and mathematical skills. A questionnaire was sent to parents, teachers and speech therapists for their views on children s language abilities, learning and future. SLI-children continued to develop their language abilities through the study-period, but didn't obtain the level of linguistic abilities of their peers in all respects. Specific difficulties persisted in word naming, difficulties with grammatical rules were also common. Despite the large individual variation in language abilities, diagnostic category F80.2 (problems in understanding) contained a larger number of weak results in language tests than diagnostic category F80.1 (problems in production). Technical reading ability declined during the study-period, at the same time reading comprehension abilities strengthened. At 3rd grade major part of children had weak skills in technical reading and ⅓ of them had weak skills in reading comprehension. Good abilities in reading were achieved by less than tenth of children. Mathematical skills developed through study-period, no specific mathematical difficulties emerged. Parents and teachers maintained a positive outlook on children s learning and future. SLI does not disappear in school-age. The clear risk for reading difficulties it carries needs to be taken into consideration in schooling SLI-children. Continued research is needed both in development of SLI and in factors contributing to the quality of life in school-aged SLI-children. In Finland, there's need for broader range of language tests for school-aged children both in research and speech therapy practice.
  • Kuoppala, Antti (Helsingin yliopisto, 2002)
  • Marjamaa, Riitta (Helsingin yliopisto, 2007)
    Background: The aging population is placing increasing demands on surgical services, simultaneously with a decreasing supply of professional labor and a worsening economic situation. Under growing financial constraints, successful operating room management will be one of the key issues in the struggle for technical efficiency. This study focused on several issues affecting operating room efficiency. Materials and methods: The current formal operating room management in Finland and the use of performance metrics and information systems used to support this management were explored using a postal survey. We also studied the feasibility of a wireless patient tracking system as a tool for managing the process. The reliability of the system as well as the accuracy and precision of its automatically recorded time stamps were analyzed. The benefits of a separate anesthesia induction room in a prospective setting were compared with the traditional way of working, where anesthesia is induced in the operating room. Using computer simulation, several models of parallel processing for the operating room were compared with the traditional model with respect to cost-efficiency. Moreover, international differences in operating room times for two common procedures, laparoscopic cholecystectomy and open lung lobectomy, were investigated. Results: The managerial structure of Finnish operating units was not clearly defined. Operating room management information systems were found to be out-of-date, offering little support to online evaluation of the care process. Only about half of the information systems provided information in real time. Operating room performance was most often measured by the number of procedures in a time unit, operating room utilization, and turnover time. The wireless patient tracking system was found to be feasible for hospital use. Automatic documentation of the system facilitated patient flow management by increasing process transparency via more available and accurate data, while lessening work for staff. Any parallel work flow model was more cost-efficient than the traditional way of performing anesthesia induction in the operating room. Mean operating times for two common procedures differed by 50% among eight hospitals in different countries. Conclusions: The structure of daily operative management of an operating room warrants redefinition. Performance measures as well as information systems require updating. Parallel work flows are more cost-efficient than the traditional induction-in-room model.
  • Toiviainen, Hanna (Helsingin yliopisto, 2007)
    Consumerism emphasises the patient s position and freedom of choice. Consumerism is being promoted by a range of phenomena occurring in society and health care. Different actors hold different views on the patient as a consumer and on his or her participation. Consumer demand is created outside the patient physician relationship and the commercialisation of services generates new expectations with respect to physician s work. More and more patients may be interested in adopting a more equal position in the care relationship, and trying to negotiate with the physician or to even dictate how he or she should be cared for. In Finland, very little research has been conducted on patients and consumers organising themselves at national system level, patients as choosers, and physicians attitudes to various consumerist phenomena or the choice made by the patient. In the empirical data for this study, the term consumer-patient refers to active consumers and patients making choices related to their clinical care prior to a physician s diagnosis. Consumer-patients are also represented by consumer and patient organisations and movements. The main research question is: How do physicians regard the care choice made by the patient? This question is addressed from a perspective encompassing patients and consumers organised activities and individuals active behaviour in health care as well as physicians experiences and their views on patients as consumers making choices related to their care. The first part (Study I), examines the patient organisation field, information sources used including the websites of such organisations, files from Finland s Slot Machine Association, RAY, a survey conducted by a Finnish television news department and interviews of patient organisations. Based on observation and a physician survey, Study II examines physicians attitudes to the idea that patients could obtain information through consumer movements about physicians care practices before seeking medical care. Studies III−IV use a physician survey to examine physicians attitudes to direct-to-consumer-advertising of prescription drugs (DTCA) and their experiences and views of patient requests related to treatments and examinations. Study V uses comparative surveys to examine the attitudes of health care professionals and the population to the introduction of new technologies in health care, using genetic screenings and tests as an example. The number of patient organisations increased, with a particular escalation as of the 1990s. The characteristics and operating methods of the organisations varied greatly. Physicians organisations adopted a negative or neutral attitude towards the consumer movements idea of distributing information on care practices, whereas individual physicians attitudes were slightly more positive. Physicians regarded direct-to-consumer-advertising of prescription drugs as negative, but took a more permissive attitude towards indirect advertising. More than every third physician considered drug advertisements in general to be harmful or useless in the distribution of drug information to patients or consumers. More than half of physicians conducting patient work reported that they (very) often encountered patients who stated upon arrival for a consultation that they wanted specific treatments or examinations, and that the number of such situations had increased. Such situations were viewed as positive with regard to the care relationship by every fifth physician and as negative by two fifths. Physicians justified a reserved attitude to the patients consumer role by referring to their medical expertise and position as care decision-makers, the patient physician relationship and the public health care system. Reasons for a positive attitude included the patient s participation and co-operation, the patient physician relationship and the patient s knowledge. Professionals were more reserved than lay people about the introduction and extension of genetic technologies in health care. A significant minority of the physicians did not take a clear pro or con attitude to the patients consumer role or to the use of new technologies in health care. The physicians age, gender, place of work and specialisation influenced their attitudes to the patient s consumer role, and private physicians viewed it in a more positive light than those working in public health care. Active consumer-patients challenge the society to hold a discussion of the patient s choice, participation in care decision-making and participation in health care policy in general. Their transformation into customers and consumers implies not only a new division of individuals roles and powers, but also contributes to changing relationships between system level roles: between citizens and the state and between public and private health care. This phenomenon raises various issues related to health care policy. In conclusion, topics are presented for discussion, practical measures and further research. Keywords: health care, consumerism, distribution of technologies, commercialisation, physicians, patients, consumers, patient s choice, patient s role.
  • Javela, Kaija (Helsingin yliopisto, 2006)
    High quality of platelet analytics requires specialized knowledge and skills. It was applied to analyze platelet activation and aggregation responses in a prospective controlled study of patients with Finnish type of amyloidosis. The 20 patients with AGel amyloidosis displayed a delayed and more profound platelet shape change than healthy siblings and healthy volunteers, which may be related to altered fragmentation of mutated gelsolin during platelet activation. Alterations in platelet shape change have not been reported in association with platelet disorders. In the rare Bernard-Soulier syndrome with Asn45Ser mutation of glycoprotein (GP) IX, the diagnostic defect in the expression of GPIb-IX-V complex was characterized in seven Finnish patients, also an internationally exceptionally large patient series. When measuring thrombopoietin in serial samples of amniotic fluid and cord blood of 15 pregnant women with confirmed or suspected fetal alloimmune thrombocytopenia, the lower limit of detection could be extended. The results approved that thrombopoietin is present already in amniotic fluid. The application of various non-invasive means for diagnosing thrombocytopenia (TP) revealed that techniques for estimating the proportion of young, i.e. large platelets, such as direct measurement of reticulated platelets and the mean platelet size, would be useful for evaluating platelet kinetics in a given patient. Due to different kinetics between thrombopoietin and increase of young platelets in circulation, these measurements may have most predictive value when measured from simultaneous samples. Platelet autoantibodies were present not only in isolated autoimmune TP but also in patients without TP where disappearance of platelets might be compensated by increased production. The autoantibodies may also persist after TP has been cured. Simultaneous demonstration of increased young platelets (or increased mean platelet volume) in peripheral blood and the presence of platelet associated IgG specificities to major glycoproteins (GPIb-IX and GPIIb-IIIa) may be considered diagnostic for autoimmune TP. Measurement of a soluble marker as a sign of thrombin activation and proceeding deterioration of platelet components was applied to analyze the alterations under several stress factors (storage, transportation and lack of continuous shaking under controlled conditions) of platelet products. The GPV measured as a soluble factor in platelet storage medium showed good correlation with an array of other measurements commonly applied in characterization of stored platelets. The benefits of measuring soluble analyte in a quantitative assay were evident.
  • Leiviskä, Jaana (Helsingin yliopisto, 2013)
    Dyslipidemia - high serum cholesterol, LDL-cholesterol (LDL-C), or triglycerides or low HDL-cholesterol (HDL-C) concentration - is one among the most important factors increasing the risk for cardiovascular disease. Apolipoprotein A-I (apoA-I) is the main apolipoprotein of atheroprotective HDL particles and apoB is the main apolipoprotein in all other atherogenic lipoprotein particles. An increased number of apoB-containing particles and low HDL-C together with almost normal LDL-C is a common feature in obesity, metabolic syndrome, and type 2 diabetes. The first aim of this study was to assess the systematic errors in cholesterol, triglycerides, and HDL-C measurements. Secondly, the effect of fasting and non-fasting triglyceride values on the prevalences of high LDL-C and metabolic syndrome was estimated. The reference intervals for apoA-I, apoB, and apoB/apoA-I ratio were calculated and they were compared with the traditional lipid and lipoprotein concentrations in different pathophysiological conditions. Finally, two direct HDL-C methods and two turbidimetric apoA-I methods in two independent laboratories were compared to discover the concordance between these methods. The data for estimating accuracy of cholesterol, triglycerides, and HDL-C measurements was obtained from different external quality assessment (EQA) programs, in which the Laboratory of Analytical Biochemistry at the National Institute for Health and Welfare has participated since 1978. The laboratory data for lipid and lipoprotein population trends was obtained from the FINRISK population-based health surveys during 1982 2012. During this time systematic error for cholesterol and triglyceride measurements remained within the range of 4% but for HDL-C error was larger. Comparison of two direct HDL-C methods showed a concentration-dependent difference between these methods. At low HDL-C concentrations difference between methods was negative -12.0 %, but at higher concentrations turned out to be positive: +9.0 %. However, apoA-I methods demonstrated better agreement than HDL-C in the method comparisons. Obese men and women had the highest apoB concentrations and apoB/apoA-I ratios compared to the healthy reference group. Men with self-reported cardiovascular disease (CVD) or diabetes had lower apoB concentrations and apoB/apoA-I ratio than the averages in the healthy reference group. In contrast women had higher apoB concentrations and apoB/apoA-I ratios in obesity, CVD, hypertension, or diabetes than in the healthy reference group. Participating in the external quality assessment programs with target values measured by the reference methods was essential, when interpreting the effects of the systematic errors on the population lipid trends. The concentration-dependent differences in homogeneous HDL-C methods may cause misclassificatios in the risk assessment of cardiovascular disease. Because an increased number of apoB-containing lipoproteins but a normal or even low LDL-cholesterol is a common feature in obesity, metabolic syndrome and type 2 diabetes, apoB measurements may produce more specific information in the risk assessment for CVD in these conditions than total cholesterol and LDL-C measurements.
  • Peuhkuri, Katri (Helsingin yliopisto, 2000)
  • Vuoristo, Sanna (Helsingin yliopisto, 2013)
    Extracellular matrix consists of complex proteins, like collagens, which primarily provide mechanical support and non-collagenous proteins, like fibronectin and laminins (LM). Essentially, extracellular matrix can be divided into interstitial matrix, where the stromal cells, growth factors and ions are embedded or basement membranes, a specialized type of extracellular matrix, which for instance segregates epithelial cells from the surrounding stroma. The first basement membranes of a mouse embryo can be detected already around 3.5 days after fertilization. Laminins initiate basement membrane assembly and are indispensable for a proper basement membrane structure and function during embryogenesis and in adulthood. Human embryonic stem cells have been cultured in vitro for fifteen years and human induced pluripotent stem cells have been reprogrammed from somatic cells since 2007. Originally, human embryonic stem cells were derived in undefined conditions. During the past decade, progress has been made in development of optimized and defined culture conditions for human pluripotent (including embryonic and induced) stem cells. However, the extracellular matrix of human pluripotent stem cells has been poorly understood. An overall aim of this thesis was to study the laminins in human pluripotent stem cells. We found that human embryonic stem cells synthesize LM-111 and -511, the first laminin isoforms synthesized also in mouse embryos. Human embryonic stem cells bound efficiently to LM-511 through integrin α3β1 heterodimer and Lutheran/basal cell adhesion molecule. We showed that undifferentiated human embryonic stem cells could be maintained on LM-511 purified from human cells and that LM-511 was essential also in feeder-dependent stem cell cultures. In large scale, human pluripotent stem cells have been mostly cultured on mouse extracellular matrix preparations. We therefore decided to optimize a novel culture matrix, based on human laminin isoforms secreted by a human carcinoma cell line. Using this novel culture matrix, we were able not only to maintain human pluripotent stem cells but also to reprogram human somatic cells to pluripotency. Adhesion of the newly formed human induced pluripotent stem cell colonies to this matrix was significantly more efficient than to commonly used feeder-free culture systems, suggesting that the matrix could be used in large-scale induced pluripotent stem cell expansion. Finally, we showed that LM α5 synthesis is dependent on the size of the stem cell colony, as well as on the position of the cell in large colonies. The data indicated that LM-511 is mostly produced in context of cell adhesion, cell spreading and migration. Knockdown of LM α5 in human pluripotent stem cells resulted in stress fiber formation in the cells and disorganization in the stem cell colonies. Moreover, the knockdown cells suffered from impaired self-renewal and colony expansion, as compared to the control cells. Taken together, our results suggest that LM-511 maintains human pluripotent stem cells in vitro by mediating cell adhesion, as well as by supporting stem cell morphology and self-renewal, likely via integrin-mediated signaling. This thesis provide essential information about how human pluripotent stem cells modify their adjacent microenvironment, especially LM-511. Based on the primary characterization of human pluripotent cells and their growth requirements, we developed a novel culture matrix, which can be utilized in various stem cell applications, especially in derivation of new induced pluripotent stem cell lines. Finally, our results regarding the functions of LM-511 in undifferentiated human pluripotent stem cells will facilitate the optimization of defined culture and differentiation protocols.
  • Teinonen, Tuomas (Helsingin yliopisto, 2009)
    Although immensely complex, speech is also a very efficient means of communication between humans. Understanding how we acquire the skills necessary for perceiving and producing speech remains an intriguing goal for research. However, while learning is likely to begin as soon as we start hearing speech, the tools for studying the language acquisition strategies in the earliest stages of development remain scarce. One prospective strategy is statistical learning. In order to investigate its role in language development, we designed a new research method. The method was tested in adults using magnetoencephalography (MEG) as a measure of cortical activity. Neonatal brain activity was measured with electroencephalography (EEG). Additionally, we developed a method for assessing the integration of seen and heard syllables in the developing brain as well as a method for assessing the role of visual speech when learning phoneme categories. The MEG study showed that adults learn statistical properties of speech during passive listening of syllables. The amplitude of the N400m component of the event-related magnetic fields (ERFs) reflected the location of syllables within pseudowords. The amplitude was also enhanced for syllables in a statistically unexpected position. The results suggest a role for the N400m component in statistical learning studies in adults. Using the same research design with sleeping newborn infants, the auditory event-related potentials (ERPs) measured with EEG reflected the location of syllables within pseudowords. The results were successfully replicated in another group of infants. The results show that even newborn infants have a powerful mechanism for automatic extraction of statistical characteristics from speech. We also found that 5-month-old infants integrate some auditory and visual syllables into a fused percept, whereas other syllable combinations are not fully integrated. Auditory syllables were paired with visual syllables possessing a different phonetic identity, and the ERPs for these artificial syllable combinations were compared with the ERPs for normal syllables. For congruent auditory-visual syllable combinations, the ERPs did not differ from those for normal syllables. However, for incongruent auditory-visual syllable combinations, we observed a mismatch response in the ERPs. The results show an early ability to perceive speech cross-modally. Finally, we exposed two groups of 6-month-old infants to artificially created auditory syllables located between two stereotypical English syllables in the formant space. The auditory syllables followed, equally for both groups, a unimodal statistical distribution, suggestive of a single phoneme category. The visual syllables combined with the auditory syllables, however, were different for the two groups, one group receiving visual stimuli suggestive of two separate phoneme categories, the other receiving visual stimuli suggestive of only one phoneme category. After a short exposure, we observed different learning outcomes for the two groups of infants. The results thus show that visual speech can influence learning of phoneme categories. Altogether, the results demonstrate that complex language learning skills exist from birth. They also suggest a role for the visual component of speech in the learning of phoneme categories.
  • Härkki-Sirén, Päivi (Helsingin yliopisto, 1999)