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  • Poikkeus, Piia (Helsingin yliopisto, 2007)
    Singleton pregnancies achieved by means of assisted reproductive treatment (ART) are associated with increased obstetric and neonatal risks in comparison with spontaneously conceived singleton pregnancies. The impact of infertility- and treatment-related factors on these risks is not properly understood. In addition, the psychological effects of infertility and its treatment on the experience of pregnancy have scarcely been studied. Thus, the aim of the present study was to evaluate the importance of infertility- and treatment-related factors on prediction of pregnancy outcome, obstetric and neonatal risks, fear-of-childbirth and pregnancy-related anxiety. The subjects consisted of infertile women who achieved a singleton pregnancy by means of in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). The control groups comprised spontaneously conceiving women with singleton gestations. Early pregnancy outcome was assessed by means of assay of serum human chorionic gonadoptrophin (hCG) in single samples. Other outcome data were collected from patient records, national Health Registers and via prospective questionnaire surveys. Viable pregnancies were associated with significantly higher serum hCG levels 12 days after embryo transfer than non-viable pregnancies. Among singleton pregnancies, aetiological subgroup, treatment type or the number of transferred embryos did not impair the predictive value of single hCG assessment. According to the register-based data, age-, parity- and socioeconomic status- adjusted risks of gestational hypertension, preterm contractions and placenta praevia were more frequent in the ART pregnancies than in the control pregnancies. Significantly higher rates of induction of delivery and Caesarean section occurred in the ART group than in the control group. The risks of preterm birth and low birth weight (LBW) were increased after ART pregnancy. Duration or aetiology of infertility, treatment type (fresh or frozen IVF or ICSI) or rank of treatment did not contribute to the risks of preterm birth or LBW. In addition, the risks of preterm birth and LBW remained elevated in spite of of the number of transferred embryos. Although mean duration of pregnancy was shorter and mean birth weight lower in the ART pregnancies than in the control pregnancies, these differences were hardly of clinical significance. Fear-of-childbirth and pregnancy-related anxiety were equally common to women conceiving by means of ART, or spontaneously. Partnership of five to ten years appeared to be protective as regards severe fear-of-childbirth, whereas long preceding infertility (≥ seven years) had the opposite effect. In conclusion, an early hCG assessment maintained its good predictive value regardless of infertility- or patient-related factors. Further, we did not recognise any infertility- or patient-related factors that would expose infertile women to increased obstetric or neonatal risks. However, a long period of infertility was associated with severe fear-of-childbirth.
  • Halonen, Kimmo (Helsingin yliopisto, 2004)
  • Laukontaus, Sani (Helsingin yliopisto, 2006)
    Ruptured abdominal aortic aneurysm (RAAA) is a life-threatening event, and without operative treatment the patient will die. The overall mortality can be as high as 80-90%; thus repair of RAAA should be attempted whenever feasible. The quality of life (QoL) has become an increasingly important outcome measure in vascular surgery. Aim of the study was to evaluate outcomes of RAAA and to find out predictors of mortality. In Helsinki and Uusimaa district 626 patients were identified to have RAAA in 1996-2004. Altogether 352 of them were admitted to Helsinki University Central Hospital (HUCH). Based on Finnvasc Registry, 836 RAAA patients underwent repair of RAAA in 1991-1999. The 30-day operative mortality, hospital and population-based mortality were assessed, and the effect of regional centralisation and improving in-hospital quality on the outcome of RAAA. QoL was evaluated by a RAND-36 questionnaire of survivors of RAAA. Quality-adjusted life years (QALYs), which measure length and QoL, were calculated using the EQ-5D index and estimation of life expectancy. The predictors of outcome after RAAA were assessed at admission and 48 hours after repair of RAAA. The 30-day operative mortality rate was 38% in HUCH and 44% nationwide, whereas the hospital mortality was 45% in HUCH. Population-based mortality was 69% in 1996-2004 and 56% in 2003-2004. After organisational changes were undertaken, the mortality decreased significantly at all levels. Among the survivors, the QoL was almost equal when compared with norms of age- and sex-matched controls; only physical functioning was slightly impaired. Successful repair of RAAA gave a mean of 4.1 (0-30.9) QALYs for all RAAA patients, although non-survivors were included. The preoperative Glasgow Aneurysm Score was an independent predictor of 30-day operative mortality after RAAA, and it also predicted the outcome at 48- hours for initial survivors of repair of RAAA. A high Glasgow Aneurysm Score and high age were associated with low numbers of QALYs to be achieved. Organ dysfunction measured by the Sequential Organ Failure Assessment (SOFA) score at 48 hours after repair of RAAA was the strongest predictor of death. In conclusion surgery of RAAA is a life-saving and cost-effective procedure. The centralisation of vascular emergencies improved the outcome of RAAA patients. The survivors had a good QoL after RAAA. Predictive models can be used on individual level only to provide supplementary information for clinical decision-making due to their moderate discriminatory value. These results support an active operation policy, as there is no reliable measure to predict the outcome after RAAA.
  • Aito, Henrikka (Helsingin yliopisto, 2004)
  • Zhou, You (Helsingin yliopisto, 2013)
    Lipids, as the major components of cell membranes, are multi-functional molecules that also critically contribute to signal transduction, transcriptional regulation and membrane trafficking. The voice from single lipid molecule mixes together to create a balancing symphony or chorus called lipid homeostasis. Disturbances in the molecular song by lipids trigger profound physiological responses, which are reflected as metabolic disorders, such as obesity, metabolic syndrome, and atherosclerosis. Hence, it is important to understand the semiotics of this molecular language. Lipid homeostasis is context-dependent and regulated coordinately by a variety of lipids per se andproteins. Oxysterol binding protein (OSBP) and its homologues (ORPs) are implicated to regulate lipid homeostasis, sterol transfer and cell signaling. In this thesis, two ORPs, ORP11 and ORP7 have been extensively studied. ORP11 is abundant in human ovary, testis, kidney, liver, stomach, brain and adipose tissue and resides at the Golgi-Late endosome interface. ORP11 forms a dimer with its close homologue, ORP9, the interaction occuring in the region of aa154-292 in ORP11 and 98-372 in ORP9, which maintains the subcellular distribution of ORP11. ORP7 interacts with GATE-16 and might be involved in autophagosome biogenesis. Excess ORP7 induces recruitment of GATE-16 from Golgi to autophagosomes. ORP7 thereby regulates the proteosome-dependent degradation of Golgi v-SNARE protein, GS28, another binding partner of GATE-16. 25-hydroxycholesterol, a ligand of ORP7, modifies GS28 protein stability, an effect which is influenced by ORP7. Being the largest endocrine organ in human body, adipose tissue is the primary place to store fat. However, there is no study to compare expression patterns of ORPs in white adipose depots and adipose cells. In this thesis, we showed that human subcutaneous and visceral adipose depots as well as Simpson-Golabi-Behmel syndrome (SGBS) adipocytes sharesimilar ORP expression patterns, indicating that the mRNA signals of ORPs in adipose tissues predominantly originate from adipocytes. During adipogenesis, ORP2, ORP3, ORP4, ORP7 and ORP8 mRNA levels were downregulated, whereas ORP11 was upregulated. Silencing of ORP11 resulted in a decreased expression of adiponectin and aP2, while overexpression of ORP8 down-regulated the aP2 mRNA. Interestingly, silencing of ORP11 and overexpression of ORP8 significantly impaired triglyceride storage in the adipocytes. Taken together, the work in this thesis identifies protein binding partners of ORPs and indicates their potential roles in protein distribution and stability, intracellular trafficking, sterol sensing, and the adipocyte phenotype.
  • Taipale, Anni (Helsingin yliopisto, 2013)
    Background:Otorhinolaryngological (ORL) diseases and hearing loss frequently occur among the children of developing countries, but they remain poorly characterized. A need therefore exists for more comprehensive understanding of the background and clinical features of these diseases in resource-poor settings. Patients and methods: Voluntary paediatric outpatients of various specialties were examined at Hospital Pediátrico in Luanda, Angola. Study participants underwent medical history-taking, a thorough physical and ORL examination, hearing screening by brainstem auditory-evoked potential (BAEP), and, at age 5 or older, pure-tone audiometry. Nasopharyngeal smears (NPS) were obtained from 102 children with respiratory symptoms and screened by polymerase chain reaction (PCR) for human rhino- (HRV) and enterovirus (HEV). We took 18 bacterial culture smears from children with chronic suppurative otitis media (CSOM). Clinical data collected were compared between 23 children with CSOM vs. 23 age- and gender-matched controls, between 61 children with sickle-cell disease (SCD) vs. 61 controls, and between 78 human immunodeficiency virus (HIV) -positive children vs. 78 controls. Results: In virus screening of 102 NPS specimens, 37 (36%) were positive: 27 (26%) for HRV alone, 3 (3%) for HEV alone, and 7 (7%) for HRV+HEV. HRV prevalence was highest during the coolest month, July, 47% (26/53), compared to 22% (8/49) (p=0.021) in April-to-June. In the CSOM study, HIV positivity occurred in 14/22 (64%) of the CSOM children vs. none of the controls (p<0.001) and tuberculosis in 8/22 (36%) vs. none (p=0.002). The most frequent CSOM pathogens were Proteus (8/18, 44%) and Pseudomonas (4/18, 22%) species. CSOM resulted in hearing loss of >25 dB HL in pure-tone averages or BAEP in 17/33 (52%) of the affected ears. In the SCD study of 61 SCD children vs. 61 controls, bilateral hearing loss of >25 dB HL at any frequency occurred in 9 (36%) SCD children vs. 3 (11%) controls (p=0.047), whereas the prevalence of other ORL findings showed no significant difference. Of 78 HIV-positive children vs. 78 controls, ORL pathology was present in 72 (92%) HIV-positive vs. 61 (72%) control children (p=0.022). Dental caries occurred in 44 (56%) of the HIV-positive children vs. 25 controls (32%) (p<0.001), cervical lymphadenopathy >1cm in 35 (45%) vs. 8 (10%) (p<0.001), facial skin lesions in 25 (32%) vs. 4 (5%) (p<0.001), CSOM in 21 (26%) vs. 3 (4%) (p<0.001), and bilateral hearing loss of >25 dB HL in PTA or BAEP in 10 (13%) vs. one (1%) (p=0.009). Conclusions: In children of tropical Luanda, HRV and HEV emerged during respiratory symptoms. CSOM was associated with co-morbidity and hearing loss. Hearing loss occurred in SCD. ORL manifestations of HIV infection were common and various. In resource-poor settings, ORL and hearing services deserve a higher priority.
  • Perttunen, Kristiina (Helsingin yliopisto, 2003)
  • Saastamoinen, Peppiina (Helsingin yliopisto, 2010)
    The overall objective of this study was to gain epidemiological knowledge about pain among employee populations. More specifically, the aims were to assess the prevalence of pain, to identify socio-economic risk groups and work-related psychosocial risk factors, and to assess the consequences in terms of health-related functioning and sickness absence. The study was carried out among the municipal employees of the City of Helsinki. Data comprised questionnaire survey conducted in years 2000-2002 and register data on sickness absence. Altogether 8960 40-60 year old employees participated to the survey (response rate 67%). Pain is common among ageing employees. Approximately 29 per cent of employees reported chronic pain and 15 per cent acute pain, and about seven per cent reported moderately or severely limiting disabling chronic pain. Pain was more common among those with lower level of education or in a low occupational class. -- Psychosocial work environment was associated with pain reports. Job strain, bullying at workplace, and problems in combining work and home duties were associated with pain among women. Among men combining work and home duties was not associated with pain, whereas organizational injustice showed associations. Pain affects functional capacity and predicts sickness absence. Those with pain reported lower level of both mental and physical functioning than those with no pain, physical functioning being more strongly affected than mental. Bodily location of pain or whether pain was acute or chronic had only minor impact on the variation in functioning, whereas the simple count of painful locations was associated with widest variation. Pain accounted for eight per cent of short term (1-3 day) sickness absence spells among men and 13 per cent among women. Of absence spells lasting between four and 14 days pain accounted for 23 per cent among women and 25 per cent among men, corresponding figures for over 14 day absence spells being 37 and 30 per cent. The association between pain and sickness absence was relatively independent of physical and psychosocial work factors, especially among women. The results of this study provide a picture of the epidemiology of pain among employees. Pain is a significant problem that seriously affects work ability. Information on risk groups can be utilized to make prevention measures more effective among those at high risk, and to decrease pain rates and thereby narrow the differences between socio-economic groups. Furthermore, the work-related psychosocial risk factors identified in this study are potentially modifiable, and it should be possible to target interventions on decreasing pain rates among employees.
  • Kuivalainen, Anna-Maria (Helsingin yliopisto, 2015)
    Background: Bone marrow aspiration and/or biopsy (BMAB) is a procedure used to diagnose and follow up various haematological diseases. It is usually performed at either the sternum or the iliac crest. The procedure often causes pain despite local infiltration anaesthesia. The objective of this study was to evaluate different means of pain relief during BMAB in adult patients. Special attention was paid to pre-procedural anxiety and its effect on pain. The commonly used local anaesthetic lidocaine was compared with articaine, an anaesthetic known for its ability to penetrate bone tissue. The effect of warming and buffering the lidocaine solution, measures expected to improve the anaesthetic action, was examined. Also investigated were sublingual fentanyl and inhaled 50% nitrous oxide (N2O) in oxygen (O2) as means of analgesia and sedation during BMAB. Patients: The patient population comprised 646 adult outpatients from the Department of Haematology, Helsinki University Central Hospital, Finland. Patients were randomized to treatment groups in trials comparing one intervention with another or with placebo. The studies were all patient-blinded. One study was observational and investigated the association between pain and pre-procedural anxiety. Patient recruitment was performed between 2007 and 2014. Main results: Pre-procedural anxiety intensified pain during BMAB in all trials. Median NRS (Numeral Rating Scale, 0 = no pain, 10 = worst pain imaginable) during infiltration was 3.0 (range 0 10, interquartile range (IQR) 3.0), puncture 2.0 (range 0 10, IQR 3.0), aspiration 4.0 (range 0 10, IQR 4.0), biopsy 4.0 (range 0 10, IQR 4.0) and immediately after BMAB 0 (range 0 9.0, IQR 1.0). Scores of 8 10 comprised 8.1%, 4.7%, 13.9%, and 12.4% of the scores for infiltration, puncture, aspiration and biopsy, respectively. Possible supplemental analgesia or sedation given on patient request in addition to local anaesthesia and study intervention did not lower pain scores during BMAB. Articaine was not found to be superior to lidocaine as a local anaesthetic. Warming and buffering the lidocaine solution diminished pain during infiltration, but did not lower the pain scores during other phases of BMAB. Sublingual fentanyl (200 µg or 100 µg) did not provide significant pain relief relative to placebo when administered 6 64 minutes before BMAB. Dizziness was a frequent side-effect. Inhalation of 50% N2O in O2 was no more effective than inhalation of 50% O2. No significant differences in adverse effects emerged between patients receiving N2O/O2 and those receiving 50% O2. Interestingly, 86% of N2O patients and 83% of placebo patients would choose the same analgesia method during their next BMAB. Conclusions: Many patients undergoing BMAB suffer intense pain during the procedure. Pre-procedural anxiety was strongly associated with pain during the various phases of BMAB. The pain from local anaesthetic infiltration with articaine and lidocaine was similar. Buffering and warming the local anaesthetic solution clearly reduced the infiltration pain. However, neither these measures nor the use of sublingual fentanyl or inhalation of N2O had an impact on the pain caused by aspiration and biopsy.
  • Pesonen, Anne (Helsingin yliopisto, 2011)
    The proportion of patients over 75 years of age, receiving all different types of healthcare, is constantly increasing. The elderly undergo surgery and anaesthetic procedures more often than middle-aged patients. Poor pain management in the elderly is still an issue. Although the elderly consumes the greatest proportion of prescribed medicines in Western Europe, most clinical pharmacological studies have been performed in healthy volunteers or middle-aged patients. The aim of this study was to investigate pain measurement and management in cognitively impaired patients in long term hospital care and in cognitively normal elderly patients after cardiac surgery. This thesis incorporated 366 patients, including 86 home-dwelling or hospitalized elderly with chronic pain and 280 patients undergoing cardiac surgery with acute pain. The mean age of patients was 77 (SD ± 8) years and approximately 8400 pain measurements were performed with four pain scales: Verbal Rating Scale (VRS), the Visual Analogue Scale (VAS), the Red Wedge Scale (RWS), and the Facial Pain Scale (FPS). Cognitive function, depression, functional ability in daily life, postoperative sedation and postoperative confusion were assessed with MMSE, GDS, Barthel Index, RASS, and CAM-ICU, respectively. The effects and plasma concentrations of fentanyl and oxycodone were measured in elderly (≥ 75 years) and middle-aged patients (≤ 60 years) and the opioid-sparing effect of pregabalin was studied after cardiac surgery. The VRS pain scores after movement correlated with the Barthel Index. The VRS was most successful in the groups of demented patients (MMSE 17-23, 11-16 and ≤ 10) and in elderly patients on the first day after cardiac surgery. The elderly had a higher plasma concentration of fentanyl at the end of surgery than younger patients. The plasma concentrations of oxycodone were comparable between the groups. Pain intensity on the VRS was lower and the sedation scores were higher in the elderly. Total oxycodone consumption during five postoperative days was reduced by 48% and the CAM-ICU scores were higher on the first postoperative day in the pregabalin group. The incidence of postoperative pain during movement was lower in the pregabalin group three months after surgery. This investigation demonstrates that chronic pain did not seem to impair daily activities in home-dwelling Finnish elderly. The VRS appeared to be applicable for elderly patients with clear cognitive dysfunction (MMSE ≤17) and it was the most feasible pain scale for the early postoperative period after cardiac surgery. After cardiac surgery, plasma concentrations of fentanyl in elderly were elevated, although oxycodone concentrations were at similar level compared to middle-aged patients. The elderly had less pain and were more sedated after doses of oxycodone. Therefore, particular attention must be given to individual dosing of the opioids in elderly surgical patients, who often need a smaller amount for adequate analgesia than middle-aged patients. The administration of pregabalin reduced postoperative oxycodone consumption after cardiac surgery. Pregabalin-treated patients had less confusion, and additionally to less postoperative pain on the first postoperative day and during movement at three months post-surgery. Pregabalin might be a new alternative as analgesic for acute postoperative and chronic pain management in the elderly. Its clinical role and safety remains to be verified in large-scale randomized and controlled studies. In the future, many clinical trials in the older category of patients will be needed to facilitate improvements in health care methods.
  • Rönty, Mikko (Helsingin yliopisto, 2008)
    Palladin is a novel actin microfilament associated protein, which together with myotilin and myopalladin forms a novel cytoskeletal IgC2 domain protein family. Whereas the expression of myotilin and myopalladin is limited mainly to striated muscle, palladin is widely expressed in both epithelial and mesenchymal tissues, including heart and the nervous system. Palladin has a complex genetic structure and it is expressed as several different sized and structured splice variants, which also display differences in their expression pattern and interactions. In muscle cells, all the family members localize to the sarcomeric Z-disc, and in non-muscle cells palladin also localizes to the stress-fiber-dense regions, lamellipodia, podosomes and focal adhesions. A common feature of this protein family is the binding to α-actinin, but other interactions are mostly unique to each member. Palladin has been shown to interact with several proteins, including VASP, profilin, Eps8, LASP-1 and LPP. Its domain structure, lack of enzymatic activity and multiple interactions define it as a molecular scaffolding protein, which links together proteins with different functional modalities into large complexes. Palladin has an important role in cytoskeletal regulation, particularly in stress fiber formation and stabilization. This assumption is supported by several experimental results. First, over-expression of palladin in non-muscle cells results in rapid reorganization of the actin cytoskeleton and formation of thick actin bundles. Second, the knock-down of palladin with anti-sense and siRNA techniques or knock-out by genetic methods leads to defective stress fiber formation. Furthermore, palladin is usually up-regulated in situations requiring a highly organized cytoskeleton, such as differentiation of dendritic cells, trophoblasts and myofibroblasts, and activation of astrocytes during glial scar formation. The protein family members have also direct disease linkages; myotilin missense mutations are the cause of LGMD1A and myofibrillar myopathy. Palladin mutations and polymorphisms, on the other hand, have been linked to hereditary pancreatic cancer and myocardial infarction, respectively. In this study we set out to characterize human palladin. We identified several palladin isoforms, studied their tissue distribution and sub-cellular localization. Four novel interaction partners were identified; ezrin, ArgBP2, SPIN90 and Src-kinase.The previously identified interaction between palladin and α-actinin was also characterized in detail. All the identified new binding partners are actin cytoskeleton associated proteins; ezrin links the plasma membrane to the cytoskeleton, ArgBP2 and SPIN90 localize, among other structures, to the lamellipodia and in cardiomyocytes to the Z-disc. Src is a transforming tyrosine kinase, which besides its role in oncogenesis has also important cytoskeletal associations. We also studied palladin in myofibroblasts, which are specialized cells involved in diverse physiological and pathological processes, such as wound healing and tissue fibrosis. We demonstrated that palladin is up-regulated during the differentiation of myofibroblasts in an isoform specific manner, and that this up-regulation is induced by TGF-β via activation of both the SMAD and MAPK signalling cascades. In summary, the results presented here describe the initial characterization of human palladin and offer a basis for further studies.
  • Ainola, Mari (Helsingin yliopisto, 2009)
    Rheumatoid arthritis is the most common of all types of arthritis and despite of intensive research etiology of the disease remains unclear. Distinctive features of rheumatic arthritis comprise continuous inflammation of synovium, in which synovial membrane expands on cartilage leading to pannus tissue formation. Pannus formation, appearance of proteolytic enzymes and osteoclast formation cause articular cartilage and bone destruction, which lead to erosions and permanent joint damage. Proteolytic pathways play major roles in the development of tissue lesions in rheumatoid arthritis. Degradation of extracellular matrix proteins is essential to pannus formation and invasion. Matrix metalloproteinases (MMP) form a large proteolytic enzyme family and in rheumatoid arthritis they contribute to pannus invasion by degrading extracellular matrix and to joint destruction by directly degrading the cartilage. MMP-1 and MMP-3 are shown to be increased during cell invasion and also involved in cartilage destruction. Increase of many cytokines has been observed in rheumatoid arthritis, especially TNF-α and IL-1β are studied in synovial tissue and are involved in rheumatoid inflammation and degradation of cartilage. Underlying bone resorption requires first demineralization of bone matrix with acid secreted by osteoclasts, which exposes the collagen-rich matrix for degradation. Cathepsin K is the best known enzyme involved in bone matrix degradation, however deficiency of this protein in pycnodysostosis patient did not prevent bone erosion and on the contrary pannus tissue invading to bone did not expressed much cathepsin K. These indicate that other proteinases are involved in bone degradation, perhaps also via their capability to replace the role of other enzymes especially in diseases like pycnodysostosis or during medication e.g. using cathepsin K inhibitors. Multinuclear osteoclasts are formed also in pannus tissue, which enable the invasion into underlying bone matrix. Pannus tissue express a receptor activator of nuclear factor kappa B ligand (RANKL), an essential factor for osteoclast differentiation and a disintegrin and a metalloproteinase 8 (ADAM8), an osteoclast-activating factors, involved in formation of osteoclast-like giant cells by promoting fusion of mononuclear precursor cells. The understanding of pannus invasion and degradation of extracellular matrix in rheumatic arthritis will open us new more specific methods to prevent this destructive joint disease.
  • Peura, Matti (Helsingin yliopisto, 2012)
    The skin is the largest organ of the human body. It maintains body homeostasis and provides an essential barrier that protects us from the environment. After injury to the skin, a complex series of tightly controlled responses are initiated to restore its integrity. In large-scale wounds, such as burns, the intrinsic capacity for healing is compromised due to lack of dermal support. Dermal fibroblasts guide crucial re-epithelialization events such as keratinocyte migration and proliferation. Fibroblast-keratinocyte interaction is directed by paracrine factors as well as cell-cell and cell-extracellular matrix contacts. Fibroblasts as well as other mesenchyme-derived cells such as bone marrow stromal cells can produce a vast array of growth factors in vitro. When activated by deprivation of extracellular matrix cell adhesion sites, the cells prefer cell-to-cell contacts, form clusters, and release growth factors. This present work focused on characterizing the use of a combination of growth factors released by mesenchymal cell aggregates, a process designated as nemosis, for treatment of skin wound healing. We used inhibitors of several intracellular signaling pathways to define the migration-inducing mechanisms of nemosis using a keratinocyte wound-healing assay. Model human keratinocytes HaCaT-cells responded to the nemosis-derived conditioned medium with enhanced migration, proliferation, and viability. A c-Met-specific small molecule tyrosine kinase inhibitor as well as an anti-hepatocyte growth factor antibody inhibited these responses. The study aimed to characterize means of improving wound healing by combining biological materials, such as fibrin or recombinant human collagen III with the growth factors to construct a transplantable cell- and growth factor-containing matrix. When we treated porcine partial-thickness wounds with the growth factor-containing fibrin matrix, we observed an increase in the proliferation and migration of hair-follicle and lateral wound-edge keratinocytes. In addition, granulation tissue formation was enhanced when compared with formation on saline-treated wounds. Keratinocyte transplantation in porcine full thickness wounds was feasible with a recombinant human collagen type III matrix. The results presented here indicate that cell-cell contact-activated fibroblasts or bone marrow stromal cells improve keratinocyte transplantation with paracrine factors. Fibrin or recombinant human collagen III can serve as vehicles for delivery of these signals to the target site in acute wounds. Since these factors are also crucial for healing of chronic non-healing wounds, it is likely that our therapeutic approach will be of benefit in their treatment, too.  
  • Björkman, Mikko (Helsingin yliopisto, 2010)
    Serum parathyroid hormone (PTH) and vitamin D are the major regulators of extracellular calcium homeostasis. The inverse association between PTH and vitamin D and the common age-related elevation of the PTH concentration are well known phenomena. However, the confounding or modifying factors of this relationship and their impact on the response of PTH levels to vitamin D supplementation need further investigation. Clinical conditions such as primary hyperparathyroidism (PHPT), renal failure and vitamin D deficiency, characterized by an elevation of the PTH concentration, have been associated with impaired long-term health outcomes. Curative treatments for these conditions have also been shown to decreases PTH concentration and attenuate some of the adverse health effects. In PHPT it has also been commonly held that hypercalcaemia, the other hallmark of the disease, is the key mediator of the adverse health outcomes. In chronic kidney disease the systemic vascular disease has been proposed to have the most important impact on general health. Some evidence also indicates that vitamin D may have significant extraskeletal actions. However, the frank elevation of PTH concentration seen in advanced PHPT and in end-stage renal failure have also been suggested to be at least partly causally related to an increased risk of death as well as cognitive dysfunction. However, the exact mechanisms have remained unclear. Furthermore, the predictive value of elevated PTH in unselected older populations has been less well studied. The studies presented in this thesis investigated the impact of age and mobility on the responses of PTH levels to vitamin D deficiency and supplementation. Furthermore, the predictive value of PTH for long-term survival and cognitive decline was addressed in an unselected population of older people. The hypothesis was that age and chronic immobility are related to a persistently blunted elevation of PTH concentration, even in the presence of chronic vitamin D deficiency, and to attenuated responses of PTH to vitamin D supplementation. It was also further hypothesized that a slightly elevated or even high-normal PTH concentration is an independent indicator of an increased risk of death and cognitive decline in the general aged population. The data of this thesis are based on three samples: a meta-analysis of published vitamin D supplementation trials, a randomized placebo controlled six-month vitamin D supplementation trial, and a longitudinal prospective cohort study on a general aged population. Based on a PubMed search, a meta-analysis of 52 clinical trials with 6 290 adult participants was performed to evaluate the impact of age and immobility on the responses of PTH to 25-OHD levels and vitamin D supplementation. A total of 218 chronically immobile, very old inpatients were also enrolled into a vitamin D supplementation trial. Mortality data for these patients was also collected after a two-year follow-up. Finally, data from the Helsinki Aging Study, which followed three random age cohorts (75, 80 and 85 years) until death in almost all subjects, was used to evaluate the predictive value of PTH for long-term survival and cognitive decline. This series of studies demonstrated that in older people without overt renal failure or severe hypercalcaemia, serum 25-OHD and PTH were closely associated, but this relationship was also affected by age and immobility. Furthermore, a substantial proportion of old chronically bedridden patients did not respond to vitamin D deficiency by elevating PTH, and the effect of a high-dose (1200 IU/d) six-month cholecalciferol supplementation on the PTH concentration was minor. This study demonstrated longitudinally for the first time that the blunted PTH also persisted over time. Even a subtle elevation of PTH to high-normal levels predicted impaired long-term health outcomes. Slightly elevated PTH concentrations indicated an increased risk of clinically significant cognitive decline and death during the last years of life in a general aged population. This association was also independent of serum ionized calcium (Ca2+) and the estimated glomerular filtration rate (GFR). A slightly elevated PTH also indicated impaired two-year survival during the terminal years of frail elderly subjects independently of Ca2+, GFR, and of 25-OHD levels. The interplay between PTH and vitamin D in the regulation of calcium homeostasis is more complex than has been generally considered. In addition to muskuloskeletal health parathyroid hormone is also related to the maintenance of other important domains of health in old age. Higher PTH concentrations, even within conventional laboratory reference ranges, seem to be an independent indicator of an increased risk of all-cause and of cardiovascular mortality, independently of established cardiovascular risk factors, disturbances in mineral metabolism, and renal failure. Limited and inconsistent evidence supports the role of vitamin D deficiency-related lack of neuroprotective effects over the causal association between PTH and impaired cognitive functions. However, the causality of these associations remains unclear. The clinical implications of the observed relationships remain to be elucidated by future studies interfering with PTH concentrations, especially by long-term interventions to reduce PTH.
  • Ray, Carola (Helsingin yliopisto, 2013)
    Daily health behaviours; a balanced diet, sufficient physical activity and night sleep, and limited sedentary behaviour, are essential for children s energy balance as well as for general well-being. Several characteristics in the family are known as determinants for daily health behaviours. Still, many gaps exist in our knowledge. Specific aims of this study were to examine 1) the associations between parent s sense of coherence (SOC) and children s eating habits, 2) whether parental warmth and responsiveness moderate the associations between parenting practices and children s daily health behaviours 3) whether a free school lunch moderates the associations between parenting practices and children s fruit and vegetable intake and 4) whether parenting practices at baseline predict a favorable change in children s daily health behaviours during an 18-month follow-up. This study was based on two data sets. The Hälsoverkstaden study was conducted among 10-to 11-year-old children in the Helsinki region in 2006 (1284 children and 816 parents participated). A follow-up was performed in 2008. The Pro Greens study was conducted in 2009 in 10 countries among 11-year-old children. This study uses data from four countries with two different school lunch policies; Finland and Sweden (n=1775) which serves a free school lunch, and Germany and the Netherlands (n=1405) with no free lunch. This study showed that a stronger parent s SOC was associated with a higher probability that the child had a regular meal pattern; eating daily breakfast, lunch and dinner, more frequent intake of nutrient-dense foods, and less frequent intake of energy-rich foods. The associations between a higher amount of parenting practices and children s regular meal pattern and intake of nutrient-dense foods were stronger when children simultaneously perceived parental warmth and responsiveness. The associations between parenting practices and intake of energy-rich foods and screen time were stronger when children did not perceive warmth and responsiveness from both of their parents. Most of the clusters of fruit and vegetable related parenting practices were more strongly associated with children s intake of raw and cooked vegetables in Germany and the Netherlands, as compared with Finland and Sweden, both of which have free school lunches. Most health behaviours changed unfavourably during the 18-month follow up. Parenting practices predicted such favourable changes in children s daily health behaviours as higher increase in physical activity, less increase in screen time and soft drink intake, and less decrease in fruit intake. This interdisciplinary thesis showed that parenting practices and parents SOC are important determinants and predictors for 10-11 -year old children s daily health behaviours. The contribution to existing knowledge is useful in families, in schools, in health care, when targeting groups with special needs for example overweight children and their families, and in planning and carrying out health policies in order to promote daily health behaviours and healthy weight status development among school-aged children.
  • Helske, Satu (Helsingin yliopisto, 2007)
    Aortic valve stenosis (AS) is an active disease process akin to atherosclerosis, with chronic inflammation, lipid accumulation, extracellular matrix remodeling, fibrosis, and extensive calcification of the valves being characteristic features of the disease. The detailed mechanisms and pathogenesis of AS are still incompletely understood, however, and pharmacological treatments targeted toward components of the disease are not currently available. In this thesis project, my coworkers and I studied stenotic aortic valves obtained from 86 patients undergoing valve replacement for clinically significant AS. Non-stenotic control valves (n=17) were obtained from patients undergoing cardiac transplantation or from organ donors without cardiac disease. We identified a novel inflammatory factor, namely mast cell, in stenotic aortic valves and present evidence showing that this multipotent inflammatory cell may participate in the pathogenesis of AS. Using immunohistochemistry and double immunofluorescence stainings, we found that a considerable number of mast cells accumulate in stenotic valves and, in contrast to normal valves, the mast cells in diseased valves were in an activated state. Moreover, valvular mast cells contained two effective proteases, chymase and cathepsin G, which may participate in adverse remodeling of the valves either by inducing fibrosis (chymase and cathepsin G) or by degrading elastin fibers in the valves (cathepsin G). As chymase and cathepsin G are both capable of generating the profibrotic peptide angiotensin II, we also studied the expression and activity of angiotensin-converting enzyme (ACE) in the valves. Using RT-PCR, imunohistochemistry, and autoradiography, we observed a significant increase in the expression and activity of ACE in stenotic valves. Besides mast cell-derived cathepsin G, aortic valves contained other elastolytic cathepsins (S, K, and V). Using immunohistochemistry, RT-PCR, and fluorometric microassay, we showed that the expression and activity of these cathepsins were augmented in stenotic valves. Furthermore, in stenotic but not in normal valves, we observed a distinctive pattern of elastin fiber degradation and disorganization. Importantly, this characteristic elastin degradation observed in diseased valves could be mimicked by adding exogenous cathepsins to control valves, which initially contained intact elastin fibers. In stenotic leaflets, the collagen/elastin ratio was increased and correlated positively with smoking, a potent AS-accelerating factor. Indeed, cigarette smoke could also directly activate cultured mast cells and fibroblasts. Next, we analyzed the expression and activity of neutral endopeptidase (NEP), which parallels the actions of ACE in degrading bradykinin (BK) and thus inactivates antifibrotic mechanisms in tissues. Real-time RT-PCR and autoradiography revealed NEP expression and activity to be enhanced in stenotic valves compared to controls. Furthermore, both BK receptors (1 and 2) were present in aortic valves and upregulated in stenotic leaflets. Isolated valve myofibroblasts expressed NEP and BK receptors, and their upregulation occurred in response to inflammation. Finally, we observed that the complement system, a source of several proinflammatory mediators and also a potential activator of valvular mast cells, was activated in stenotic valves. Moreover, receptors for the complement-derived effectors C3a and C5a were expressed in aortic valves and in cultured aortic valve myofibroblasts, in which their expression was induced by inflammation as well as by cigarette smoke. In conclusion, our findings revealed several novel mechanisms of inflammation (mast cells and mast cell-derived mediators, complement activation), fibrosis (ACE, chymase, cathepsin G, NEP), and elastin fiber degradation (cathepsins) in stenotic aortic valves and highlighted these effectors as possible pathogenic contributors to AS. These results support the notion of AS as an active process with inflammation and extracellular matrix remodeling as its key features and identify possible new targets for medical therapy in AS.
  • Marbacher, Serge (Helsingin yliopisto, 2014)
    Background and Purpose: Subarachnoid hemorrhage attributable to saccular intracranial aneurysm (IA) rupture is a devastating disease leading to stroke, permanent neurological damage and death. Despite rapid advances in the development of endovascular treatment (EVT), complete and long lasting IA occlusion remains a challenge, especially in complexly shaped and large-sized aneurysms. Intraluminal thrombus induced by EVT may recanalize. The biological mechanisms predisposing IA to recanalize and grow are not yet fully understood, and the role of mural cell loss in these processes remains unclear. To elucidate these processes, animal models featuring complex aneurysm architecture and aneurysm models with different wall conditions (such as mural cell loss) are needed. Materials and Methods: Complex bilobular, bisaccular and broad-neck venous pouch aneurysms were microsurgically formed at artificially created bifurcations of both common carotid arteries in New Zealand rabbits. Sidewall aneurysms were microsurgically created on the abdominal aorta in Wistar rats. Some sidewall aneurysms were decellularized with sodium dodecyl sulfate. Thrombosis was induced using direct injection of a fibrin polymer into the aneurysm. CM-Dil-labeled syngeneic smooth muscle cells were injected into fibrin embolized aneurysms. The procedures were followed up with two-dimensional intra-arterial digital subtraction angiography, contrast-enhanced serial magnetic resonance angiographies, endoscopy, optical projection tomography, histology and immunohistochemistry. Results: Aneurysm and parent vessel patency of large aneurysms with complex angioarchitecture was 90% at one month and 86% at one year follow-up in the bifurcation rabbit model. Perioperative and one month postoperative mortality and morbidity were 0% and 9%. Mean operation time in the rat model was less than one hour and aneurysm dimensions proved to be highly standardized. Significant growth, dilatation or rupture of the experimental aneurysms was not observed, with a high overall patency rate of 86% at three week follow-up. Combined surgery-related mortality and morbidity was 9%. Decellularized aneurysms demonstrated a heterogeneous pattern of thrombosis, thrombus recanalization and growth, with ruptures in the sidewall rat model. Aneurysms with intraluminal local cell replacement at the time of thrombosis developed better neointima, showed less recurrence or growth and no ruptures. Growing and ruptured aneurysms demonstrated marked adventitial fibrosis and inflammation, complete wall disruption and increased neutrophil accumulation in unorganized luminal thrombus. Conclusions: Creation of complex venous pouch bifurcation aneurysms in the rabbit is feasible, with low morbidity, mortality and high short-term and long-term aneurysm patency. They represent a promising approach for in vivo animal testing of novel endovascular therapies. The sidewall aneurysm rat model is a quick and consistent method to create standardized aneurysms. Aneurysms missing mural cells are incapable of organizing a luminal thrombus, leading to aneurysm recanalization and increased inflammatory reactions. These, in turn, result in severe wall degeneration, aneurysm growth and eventual rupture. The results of the presented studies suggest that the biologically active luminal thrombus drives the healing process towards destructive wall remodeling and aneurysm rupture. Local smooth muscle cell transplantation compensates for mural cell loss and reduces recurrence, growth and rupture rate in a sidewall aneurysm rat model.