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  • Mildh, Leena (Helsingin yliopisto, 2007)
    Opioids are most commonly used for treatment of severe pain. However, the fear of respiratory depression has restricted the use of opioids. Depending on the monitoring system used, different modes of opioid respiratory effects have been noted in previous studies. All opioids also cause alterations in hemodynamics at least to some extent. The main goal of this series of investigations was to elucidate the native ventilatory and hemodynamic effects of different opioids. Studies I-IV each involved 8 healthy male volunteers. Study V involved 13 patients with lower or upper extremity traumas. The opioids studied were morphine, oxycodone, pethidine, fentanyl, alfentanil, tramadol and ketamine. The respiratory parameters used in this study were breathing pattern measured with respiratory inductive plethysmography, gas exchange measured with indirect calorimetry, blood gas analysis and pulse oximetry. Hemodynamics was measured with arterial blood pressure, heart rate and oxygen consumption. Plasma catecholamine and histamine concentrations were also determined. All opioids studied caused an alteration in respiratory function. Respiratory rate, alveolar ventilation and minute ventilation decreased, while tidal volume increased in most situations. Breathing pattern was also significantly affected after opioid administration. The respiratory depression caused by oxycodone was deeper than the one caused by same dose of morphine. An equianalgesic dose of tramadol caused markedly smaller respiratory depression compared to pethidine. The potency ratio for respiratory depression of fentanyl and alfentanil is similar to analgesic potency ratio studied elsewhere. Racemic ketamine attenuated the respiratory depression caused by fentanyl, if measured with minute ventilation. However, this effect was counteracted by increased oxygen consumption. Supplemental oxygen did not offer any benefits, nor did it cause any atelectasis when given to opioid treated trauma patients. Morphine caused a transient hemodynamic stimulation, which was accompanied by an increase in oxygen consumption. Oxycodone, alfentanil, fentanyl, tramadol and pethidine infusions had minimal effects on hemodynamics. Plasma catecholamine concentrations were increased after high dose opioid administration. Plasma histamine concentrations were not elevated after morphine nor oxycodone administration. Respiratory depression is a side effect noted with all opioids. The profile of this phenomenon is quite similar with different opioid-receptor agonists. The hemodynamic effects of opioids may vary depending on the opioid used, morphine causing a slight hemodynamic stimulation. However, all opioids studied could be considered hemodynamically stable.
  • Louhelainen, Marjut (Helsingin yliopisto, 2010)
    Suun kautta annosteltava kalsiumherkistäjä parantaa sydämen vajaatoimintaan liittyvää pumppausvajetta kokeellisissa sydämen vajaatoimintamalleissa Huolimatta viime vuosikymmenien lääketieteellisestä kehityksestä krooninen sydämen vajaatoiminta on silti edelleen vakava, elämänlaatua voimakkaasti rajoittava sairaus. Kalsiumherkistäjät ovat uusi, sydämen pumppausvoimaa lisäävä lääkeryhmä. Levosimendaani, kotimaista alkuperää oleva kalsiumherkistäjä, on kliinisessä käytössä akuutin vajaatoiminnan hoitoon suonensisäisesti ja lyhytaikaisesti annosteltavana valmisteena. Levosimendaanilla on aktiivinen metaboliitti, OR-1896, jonka oletetaan olevan vuorokauden mittaisen levosimendaani-infuusion jälkeen havaittujen useita päiviä kestävien hyödyllisisten vaikutuksisten takana. Levosimendaanin kroonisen, suun kautta tapahtuvan annostelun vaikutuksista tieto on vähäisempää, mutta sillä näyttää olevan positiivisia vaikutuksia potilaiden raportoimana. FM Marjut Louhelainen on selvittänyt väitöskirjassaan suun kautta annosteltavan levosimendaanin ja sen pitkäkestoisen aktiivisen metaboliitin vaikutuksia kroonisen vajaatoiminnan hoidossa käyttämällä sekä hypertensiivisen sydäntaudin että 2 tyypin diabeteksen komplisoimaan sydäninfarktin kokeellisia malleja. Tutkimuksessa selvitettiin lisäksi vajaatoimintaan johtavia molekyylitason tapahtumia sydänlihaksessa. Tutkimuksessa osoitettiin, että krooninen suun kautta annosteltu hoito sekä kalsiumherkistäjä levosimendaanilla että sen aktiivisella metaboliitilla estää hypertensiiviseen sydämen vajaatoiminnan aikaasaamaa sydämen uudelleenmuovaantumista ja siihen liittyvää kuolleisuutta. Nämä vaikutukset välittyivät vähentyneen sydänlihassoluhypertrofian, solukuolleisuuden ja neurohumaraalisen aktivaation kautta. Levosimendaanin ja OR-1896:n osoitettiin myös parantavan sydämen pumppausfunktiota tyyppi 2 diabeteksen komplisoimassa sydäninfarktissa. Ei-diabeettiseen tilanteeseen verrattuna diabetekseen liittyvä infarktin jälkeinen vajaatoiminnan kehitys oli yhteydessä lisääntyneeseen tulehdukseen, fibroosiin, solukuolemaan, neurohumoraaliseen aktivaatioon ja ennenaikaiseen kudoksen vanhenemiseen. Sekä levosimendaani, että OR-1869 vähensivät tulehduksen, fibroosin ja solukuoleman merkkejä ja vaimensi neurohumoraalista aktivaatiota. OR-1896 myös vähensi solujen vanhenemiseen liittyvien merkkiaineiden ilmentymistä. Väitöskirjassa todettiin, että suun kautta annosteltuna sekä levosimendaani, että sen aktiivinen metaboliitti OR-1896, omaavat terapeuttista potentiaalia sekä hypertensiivisen sydäntaudin hoitoon että sydäninfarktin jälkeisen vajaatoiminnan estoon. FM Marjut Louhelaisen farmakologian alaan kuuluva väitöskirja Effects of oral calcium sensitizers on experimental heart failure tarkastetaan Helsingin yliopiston Lääketieteellisessä tiedekunnassa perjantaina 29.01.2010 klo 12 (Biomedicum Helsinki, luentosali 2, Haartmaninkatu 8, Helsinki). Vastaväittäjänä toimii professori Raimo Tuominen, Helsingin yliopiston Farmasian tiedekunnasta ja kustoksena professori Eero Mervaala Helsingin yliopiston Lääketieteellisestä tiedekunnasta.
  • Hautamäki, Hanna (Helsingin yliopisto, 2014)
    Hot flushes, the most characteristic symptoms in menopause, are encountered by c.a. 80% of women. Hot flushes and other menopausal complaints can significantly impair a woman s quality of life. Additionally, the majority of women experience premenstrual symptoms in their fertile age. Due to the resemblance between premenstrual and menopausal symptoms, women with severe premenstrual symptoms might fear for an increased risk of developing menopausal complaints, such as vasomotor symptoms. It is, however, unclear why some women experience intolerable hot flushes while others remain completely asymptomatic. Hot flushes are characterised by cardiovascular reactions such as rapid episodes of reddening of skin and palpitations. Thus, women with or without hot flushes may differ in their cardiovascular reactivity and responses to hormone therapy. The present study was designed to investigate the impact of hot flushes and different forms of hormone therapy on health-related quality of life and cardiovascular autonomic function. Therefore, 150 healthy, recently postmenopausal women showing a large variation in hot flushes were studied before and during six months of hormone therapy. Hot flushes were evaluated prospectively with a two-week hot flush diary. The relationship between a history of premenstrual symptoms and the postmenopausal quality of life and hot flushes was also assessed. The cardiovascular autonomic function was studied with a standardised test series in controlled laboratory settings. Hot flushes were important determinants for the decreased health-related quality of life in menopause. Previous premenstrual symptoms lacked correlation with the severity of postmenopausal hot flushes but associated with deterioration of health-related quality of life, seen as poor sleep, depressive feelings and impaired memory and concentration. Women with hot flushes reacted with more tachycardia and slightly blunted parasympathetic activity in heart rate responses to cardiovascular autonomic testing compared with asymptomatic women. In a randomized study, all hormone therapy regimens alleviated hot flushes and other menopausal symptoms equally effectively. In women with pre-treatment hot flushes, hormone therapy improved health-related quality of life in terms of sleep, anxiety and fears, memory and concentration, and general health. Hot flushes were accompanied with lowered resting blood pressures but increases in blood pressure responses to physical strain during all hormone therapy regimens. Estradiol treatment lowered resting heart rate and reduced maximal heart rate in response to physical strain in women with pre-treatment hot flushes. This beneficial effect on heart rate was attenuated by adding medroxyprogesterone acetate to estradiol treatment. In conclusion, the hot flush status and hormone therapy contribute to cardiovascular autonomic function. Hot flushes seem to associate with slightly pronounced sympathetic responses in autonomic regulation of heart rate and blood pressure, which can be considered unbeneficial for cardiovascular function. This possibly unfavourable sympathetic activity can be reduced with estradiol treatment especially in women with hot flushes, who are potential candidates for hormone therapy in clinical practice. Hot flushes impair the health-related quality of life in recently postmenopausal women, but can be effectively alleviated with hormone therapy. Premenstrual symptoms do not predict severe hot flushes in menopause, which is comforting for women having troublesome premenstrual symptoms.
  • Vakkuri, Anne (Helsingin yliopisto, 2000)
  • Viskari-Lähdeoja, Suvi (Helsingin yliopisto, 2013)
    Background and aims. Sudden infant death syndrome (SIDS) is a rare lethal event occurring in 0.1 to 0.3 of infants. In Finland, 10 to 20 infants die from SIDS annually. Research has defined many risk factors for SIDS, but the cascade leading to death remains unexplained. Cardiovascular recordings of infants succumbing to SIDS, as well as animal models, suggest that the final sequelae involve cardiovascular collapse resembling hypotensive shock. There is also evidence of previous hypoxia in SIDS infants. In animal studies, vestibulo-mediated cardiovascular control has been shown to be important in hypotensive shock. Hence, we hypothetized that SIDS victims may have impaired vestibulo-mediated cardiovascular control, possibly due to previous hypoxic episodes. In this thesis, we studied cardiovascular control, and especially vestibulo-mediated cardiovascular control in infants with known risk factors for SIDS at 2 to 4 months of age when the risk for SIDS is highest. Study subjects. A full polysomnographic recording with continuous blood pressure (BP) measurement was performed in 50 infants at 2-4 months of age: 20 control infants, nine infants with univentricular heart (UVH) suffering from chronic hypoxia, 10 infants with bronchopulmonary dysplasia (BPD) with intermittent postnatal hypoxic events, and 11 infants whose mothers had smoked during pregnancy, and thus had been exposed to intrauterine hypoxia and nicotine, were studied. In addition, 20 preterm infants were studied at the gestational age of 34-39 weeks to evaluate developmental aspects of cardiovascular control during head-up tilt test and vestibular stimulus. Methods. Linear side motion and 45° head-up tilt tests were performed in quiet non-rapid eye movement sleep (NREM). Heart rate (HR) and BP responses were analysed from the tests without signs of subcortical or cortical arousal. In addition, HR variability during NREM sleep was assessed. As a general marker of cardiovascular reactivity, HR response to spontaneous arousal from NREM sleep was also evaluated. Results.Side motion test. In the side motion test, control infants presented a biphasic response. First, there was a transient increase in HR and BP. This was followed by a decrease in BP to below baseline, and a return to baseline in HR. All other infant groups showed altered responses. UVH infants and preterm infants near term age had markedly reduced responses. Infants with BPD presented with variable responses: some responded similarly to controls, whereas others showed no initial increase in BP, and the following BP decrease was more prominent. Infants with intrauterine exposure to cigarette smoke showed flat initial BP responses, and the following decrease was more prominent, similarly to a subgroup of BPD infants. Tilt test. Control infants presented with a large variability in BP responses to head-up tilting. On average, systolic BP remained, at first, close to baseline, and diastolic BP increased, after which both decreased and remained below baseline even at the end of the tilt test. On average, HR showed a biphasic response with an initial increase followed by a decrease to below and, finally, a return to baseline. UVH infants showed a similar BP response, but their HR response was tachycardic. Preterm infants with BPD presented with an even greater variability in their BP responses to head-up tilts than control infants, but the overall response as a group did not differ from that of the controls. The tilt response of infants exposed to maternal cigarette smoking during pregnancy did not markedly differ from the control response. Preterm infants near term age showed attenuated responses in both cardiovascular measures, together with greater inter-subject variability compared to the control infants. Discussion. In conclusion, the studied infants with SIDS risk factors showed altered vestibulo-mediated cardiovascular control during the linear side motion test and head-up tilt test. The findings support our initial hypothesis that some infants with SIDS risk factors have defective vestibulo-mediated cardiovascular control, which may lead to death in life-threatening situations.
  • Kalliokoski, Annikka (Helsingin yliopisto, 2008)
    Organic anion-transporting polypeptide 1B1 (OATP1B1), encoded by the SLCO1B1 gene, is an influx transporter expressed on the sinusoidal membrane of human hepatocytes. The common c.521T>C (p.Val174Ala) single-nucleotide polymorphism (SNP) of the SLCO1B1 gene has been associated with reduced OATP1B1 transport activity in vitro and increased plasma concentrations of several of its substrate drugs in vivo in humans. Another common SNP of the SLCO1B1 gene, c.388A>G (p.Asn130Asp), defining the SLCO1B1*1B (c.388G-c.521T) haplotype, has been associated with increased OATP1B1 transport activity in vitro. The aim of this thesis was to investigate the role of SLCO1B1 polymorphism in the pharmacokinetics of the oral antidiabetic drugs repaglinide, nateglinide, rosiglitazone, and pioglitazone. Furthermore, the effect of the SLCO1B1 c.521T>C SNP on the extent of interaction between gemfibrozil and repaglinide as well as the role of the SLCO1B1 c.521T>C SNP in the potential interaction between atorvastatin and repaglinide were evaluated. Five crossover studies with 2-4 phases were carried out, with 20-32 healthy volunteers in each study. The effects of the SLCO1B1 c.521T>C SNP on single doses of repaglinide, nateglinide, rosiglitazone, and pioglitazone were investigated in Studies I and V. In Study II, the effects of the c.521T>C SNP on repaglinide pharmacokinetics were investigated in a dose-escalation study, with repaglinide doses ranging from 0.25 to 2 mg. The effects of the SLCO1B1*1B/*1B genotype on repaglinide and nateglinide pharmacokinetics were investigated in Study III. In Study IV, the interactions of gemfibrozil and atorvastatin with repaglinide were evaluated in relation to the c.521T>C SNP. Plasma samples were collected for drug concentration determinations. The pharmacodynamics of repaglinide and nateglinide was assessed by measuring blood glucose concentrations. The mean area under the plasma repaglinide concentration-time curve (AUC) was ~70% larger in SLCO1B1 c.521CC participants than in c.521TT participants (P ≤ 0.001), but no differences existed in the pharmacokinetics of nateglinide, rosiglitazone, and pioglitazone between the two genotype groups. In the dose-escalation study, the AUC of repaglinide was 60-110% (P ≤ 0.001) larger in c.521CC participants than in c.521TT participants after different repaglinide doses. Moreover, the AUC of repaglinide increased linearly with repaglinide dose in both genotype groups (r > 0.88, P 0.001). The AUC of repaglinide was ~30% lower in SLCO1B1*1B/*1B participants than in SLCO1B1*1A/*1A (c.388AA-c.521TT) participants (P = 0.007), but no differences existed in the AUC of nateglinide between the two genotype groups. In the drug-drug interaction study, the mean increase in the repaglinide AUC by gemfibrozil was ~50% (P = 0.002) larger in c.521CC participants than in c.521TT participants, but the relative (7-8-fold) increases in the repaglinide AUC did not differ significantly between the genotype groups. In c.521TT participants, atorvastatin increased repaglinide peak plasma concentration and AUC by ~40% (P = 0.001) and ~20% (P = 0.033), respectively. In each study, after repaglinide administration, there was a tendency towards lower blood glucose concentrations in c.521CC participants than in c.521TT participants. In conclusion, the SLCO1B1 c.521CC genotype is associated with increased and the SLCO1B1*1B/*1B genotype with decreased plasma concentrations of repaglinide, consistent with reduced and enhanced hepatic uptake, respectively. Inhibition of OATP1B1 plays a limited role in the interaction between gemfibrozil and repaglinide. Atorvastatin slightly raises plasma repaglinide concentrations, probably by inhibiting OATP1B1. The findings on the effect of SLCO1B1 polymorphism on the pharmacokinetics of the drugs studied suggest that in vivo in humans OATP1B1 significantly contributes to the hepatic uptake of repaglinide, but not to that of nateglinide, rosiglitazone, or pioglitazone. SLCO1B1 polymorphism may be associated with clinically significant differences in blood glucose-lowering response to repaglinide, but probably has no effect on the response to nateglinide, rosiglitazone, or pioglitazone.
  • Porthan, Kimmo (Helsingin yliopisto, 2011)
    Electric activity of the heart consists of repeated cardiomyocyte depolarizations and repolarizations. Abnormalities in repolarization predispose to ventricular arrhythmias. In body surface electrocardiogram, ventricular repolarization generates the T wave. Several electrocardiographic measures have been developed both for clinical and research purposes to detect repolarization abnormalities. The study aim was to investigate modifiers of ventricular repolarization with the focus on the relationship of the left ventricular mass, antihypertensive drugs, and common gene variants, to electrocardiographic repolarization parameters. The prognostic value of repolarization parameters was also assessed. The study subjects originated from a population of more than 200 middle-aged hypertensive men attending the GENRES hypertension study, and from an epidemiological survey, the Health 2000 Study, including more than 6000 participants. Ventricular repolarization was analysed from digital standard 12-lead resting electrocardiograms with two QT-interval based repolarization parameters (QT interval, T-wave peak to T-wave end interval) and with a set of four T-wave morphology parameters. The results showed that in hypertensive men, a linear change in repolarization parameters is present even in the normal range of left ventricular mass, and that even mild left ventricular hypertrophy is associated with potentially adverse electrocardiographic repolarization changes. In addition, treatments with losartan, bisoprolol, amlodipine, and hydrochlorothiazide have divergent short-term effects on repolarization parameters in hypertensive men. Analyses of the general population sample showed that single nucleotide polymorphisms in KCNH2, KCNE1, and NOS1AP genes are associated with changes in QT-interval based repolarization parameters but not consistently with T-wave morphology parameters. T-wave morphology parameters, but not QT interval or T-wave peak to T-wave end interval, provided independent prognostic information on mortality. The prognostic value was specifically related to cardiovascular mortality. The results indicate that, in hypertension, altered ventricular repolarization is already present in mild left ventricular mass increase, and that commonly used antihypertensive drugs may relatively rapidly and treatment-specifically modify electrocardiographic repolarization parameters. Common variants in cardiac ion channel genes and NOS1AP gene may also modify repolarization-related arrhythmia vulnerability. In the general population, T-wave morphology parameters may be useful in the risk assessment of cardiovascular mortality.
  • Vesterinen, Paula (Helsingin yliopisto, 2007)
    The aim of the studies was to improve the diagnostic capability of electrocardiography (ECG) in detecting myocardial ischemic injury with a future goal of an automatic screening and monitoring method for ischemic heart disease. The method of choice was body surface potential mapping (BSPM), containing numerous leads, with intention to find the optimal recording sites and optimal ECG variables for ischemia and myocardial infarction (MI) diagnostics. The studies included 144 patients with prior MI, 79 patients with evolving ischemia, 42 patients with left ventricular hypertrophy (LVH), and 84 healthy controls. Study I examined the depolarization wave in prior MI with respect to MI location. Studies II-V examined the depolarization and repolarization waves in prior MI detection with respect to the Minnesota code, Q-wave status, and study V also with respect to MI location. In study VI the depolarization and repolarization variables were examined in 79 patients in the face of evolving myocardial ischemia and ischemic injury. When analyzed from a single lead at any recording site the results revealed superiority of the repolarization variables over the depolarization variables and over the conventional 12-lead ECG methods, both in the detection of prior MI and evolving ischemic injury. The QT integral, covering both depolarization and repolarization, appeared indifferent to the Q-wave status, the time elapsed from MI, or the MI or ischemia location. In the face of evolving ischemic injury the performance of the QT integral was not hampered even by underlying LVH. The examined depolarization and repolarization variables were effective when recorded in a single site, in contrast to the conventional 12-lead ECG criteria. The inverse spatial correlation of the depolarization and depolarization waves in myocardial ischemia and injury could be reduced into the QT integral variable recorded in a single site on the left flank. In conclusion, the QT integral variable, detectable in a single lead, with optimal recording site on the left flank, was able to detect prior MI and evolving ischemic injury more effectively than the conventional ECG markers. The QT integral, in a single-lead or a small number of leads, offers potential for automated screening of ischemic heart disease, acute ischemia monitoring and therapeutic decision-guiding as well as risk stratification.
  • Gross, Andres (Helsingin yliopisto, 2007)
    This work studies the effect of clozapine (CLO) on the electroencephalography (EEG) and reactive oxygen species (ROS) production by peripheral blood monocytes (MO) in patients with schizophrenia (SCH). The aim of the study was to investigate the mechanism of action of CLO, to clarify the effect of CLO on EEG absolute power spectrum and ROS production, and explore the relationship of these effects with clinical response. We also tried to clarify whether the EEG changes or ROS production would help to identify the patients who were most likely to respond to treatment with CLO. Our findings suggest that the amount of slow background activity, particularly the absolute power of the theta frequency band, in the EEG is markedly increased by CLO treatment and this finding correlates positively with clinical improvement in patients with SCH. CLO affected the production of ROS by blood MO with reduction or minimal increase of the ROS production being associated with clinical improvement, whereas marked increase of the ROS production did not. Also a positive correlation between theta absolute power increase in the EEG and suppression of the production of ROS by blood MO was found. The correlations between different symptom clusters of SCH and the EEG rhythms were investigated; the absolute power of beta activity in the EEG seemed to correlate positively to overall psychopathology in patients with SCH showing inadequate response. The results suggest that the EEG background activity and investigation of the production of ROS by MO seem to be an adjunctive method to objectively assess and possibly predict the therapeutic effect of CLO in patients with chronic SCH showing inadequate response to treatment with conventional antipsychotics.
  • Oinonen, Annamari (Helsingin yliopisto, 2009)
    Chronic venous disease (CVD), including uncomplicated varicose veins and chronic venous insufficiency, is one of the most common medical conditions in the Western world. The central feature of CVD is venous reflux, which may be primary, congenital, or result from an antecedent event, usually an acute deep venous thrombosis (DVT). When the history of DVT is clear, the clinical manifestations of secondary CVD are commonly referred to as the post-thrombotic syndrome. Regardless of the underlying etiology, the final pathway leading to symptoms is ambulatory venous hypertension. The spectrum of symptoms and signs of CVD ranges from minor cosmetic problems to venous ulceration, which results in considerable morbidity and increased medical costs. Aims of this study were to evaluate the outcome of superficial venous surgery performed with or without preoperative duplex evaluation and venous marking with hand-held doppler, to assess short-term outcome of ultrasound-guided foam sclerotherapy in patients with axial superficial venous incompetence, as well as to compare reflux patterns after catheter-directed and systemic thrombolysis of deep ileofemoral venous thrombosis, and to evaluate the long-term outcome of deep venous reconstructions for severe chronic venous insufficiency. The study consists of five separate retrospective projects and includes 315 patients. Of this, 133 patients had undergone superficial venous surgery 2 to 5 years earlier according to preoperative duplex examination and venous marking, or according to clinical evaluation alone, or to a written plan without venous marking. A total of 112 patients had undergone ultrasound-guided foam sclerotherapy 5.5 to 16.5 months before. In addition, 32 patients had received either catheter-directed or systemic thrombolysis for DVT 2 to 3 years earlier, and 38 patients had undergone deep venous reconstructions 2 to 7 years earlier. In the present studies, some venous reflux was present postoperatively irrespective of the method of evaluation or ablation of the reflux. It seemed, however, that preoperative examination with duplex ultrasound and marking of reflux sites before the operation by the operating surgeon improves the outcome of superficial venous surgery. Ultrasound-guided foam sclerotherapy is effective in elimination of venous reflux in selected cases in short-term follow-up. Catheter-directed thrombolysis for deep iliofemoral venous thrombosis reduces later reflux and most probably the development of post-thrombotic syndrome as well. The outcome of deep venous reconstructions, especially for post-thrombotic deep venous incompetence, is poor. Thus, prevention of valvular damage by active treatment of deep venous thrombosis is important.
  • Hyrskyluoto, Alise (Helsingin yliopisto, 2014)
    Huntington s disease (HD) is a fatal neurodegenerative disease with progressive motor dysfunction, cognitive decline and psychiatric disturbances. HD is caused by a CAG repeat expansion in the huntingtin (IT15) gene, which encodes the huntingtin protein. Mutations in huntingtin cause accumulation of protein aggregates with subsequent cell death and loss of neurons in the striatum and cortex. The exact molecular mechanisms by which mutant huntingtin (mHTT) induces cell death are not completely understood. Huntingtin protein participates in many cellular functions such as protein trafficking, transcriptional regulation and apoptosis. Mutant protein is cleaved to form N-terminal fragments containing the first 100-150 residues including the polyglutamine repeats, which are thought to be the toxic species found in aggregates. Previous studies have shown that endoplasmic reticulum (ER) stress is involved in the early pathogenesis of HD. However, the precise mechanisms by which mHTT proteins cause ER stress are still unclear. The aim of this thesis was to elucidate the early pathological changes in HD. The specific goal was to study in more detail how ER stress, alterations in autophagy and ubiquitin proteasome system and oxidative stress trigger the disease and by which mechanisms. This thesis also aimed to identify novel therapeutic targets for early pathogenic changes in HD. The results showed that growth arrest and DNA damage inducible gene 34 (GADD34) plays an important role in cell protection and mediates cytoprotective autophagy via the mammalian target of rapamycin (mTOR) pathway in mHTT expressing cells. Modulation of GADD34 may thus prove useful in counteracting cell degeneration accompanying HD. Our results also showed that the sigma-1 receptor (Sig1R) agonist PRE084 increased levels of cellular antioxidants by affecting the NF-κB pathway that is reduced by expression of mHTT proteins. The Sig1R agonist increased cell survival and counteracted the deleterious effects caused by N-terminal mHTT proteins. Compounds that influence the Sig1R may have beneficial effects in models of HD, which warrants further studies. This thesis also shows that overexpression of ubiquitin-specific protease-14 (Usp14) reduces cellular aggregates in mHTT expressing cells mainly via the ubiquitin proteasome system. Overexpression of Usp14 was able to inhibit phosphorylation of inositol requiring enzyme 1 (IRE1) in mHTT expressing cells and to protect against cell degeneration and caspase-3 activation. These results show ER stress induced IRE1 activation is part of mHTT toxicity, which is inhibited by Usp14.
  • Keränen, Ilona (Helsingin yliopisto, 2013)
    Gastric outlet obstruction (GOO) is a preterminal event in incurable malignancies of the gastrointestinal tract. Pancreatic cancer and gastric cancer are the most common causes for GOO. Colorectal cancer (CRC) is the most common etiology for colorectal obstruction (CRO). Other causes for CRO include extracolonic malignancies (ECM) and benign causes. Traditional treatment of GOO and CRO is surgery, but it carries a high rate of complications. Self-expanding metal stents (SEMS) have become an alternative for surgery in GOO and CRO. The aim of this work was to evaluate the results of endoscopic stenting (ES) in GOO and CRO. The study material consisted of 323 patients with GOO or CRO treated at Meilahti Hospital between January 1998 and December 2010. In study I, 104 patients with incurable GOO were included in the analysis. The study II population consisted of 97 patients with advanced gastric cancer and GOO, and of these 50 underwent ES, 26 palliative resection (PR), and 21 gastrojejunostomy (GJ). In study III, 21 patients with benign CRO were included in the analysis. The study IV population comprised 101 patients with malignant CRO, and of these 11 were stented as a bridge to surgery. In study IV, 66 underwent palliative stenting due to CRC and 24 due to ECM. In study I, a median GOOSS (gastric outlet scoring system) improved significantly from 0 to 2 after stenting, and 73% of the patients managed with one stenting procedure until death. In study II, ES resulted in a more rapid improvement in oral intake and a shorter hospital stay than GJ or PR. Complication rates were similar between the groups. In the PR group, symptom-free and overall survivals were longest. In multivariate survival analysis, independent prognostic factors were age, BMI, pre-procedure GOOSS, PR as treatment modality, and chemotherapy. In study III, 63% of anastomotic strictures (AS) were resolved with SEMS. Of diverticular strictures (DS), 30% were resolved with SEMS. Complication rate was 43%. Of the complications, 67% occurred for patients with DS or Crohn`s disease strictures. In study IV, a primary anastomosis rate in elective operations was 90% in the bridge to surgery group. In palliative stenting, clinical success rates were significantly lower for patients with ECM than for patients with CRC (63% vs. 94%, p<0.001). Between palliation groups, complication, operation, and stoma rates were similar. SEMS provides good palliation for patients with incurable GOO. In advanced gastric cancer and GOO, SEMS is a treatment of choice for patients unfit for surgery. PR seems to provide survival benefit, and should be considered as a treatment option for patients fit for surgery. In benign CRO, SEMS is a good treatment option in AS for selected patients. In DS and Crohn`s disease strictures, a high rate of complications limit the utility of SEMS. In malignant CRO, SEMS can be used as a bridge to surgery and as palliation. A higher clinical failure rate is associated with palliative stenting for ECM than for CRC.
  • Pitkäjärvi, Mari-Anne (Helsingin yliopisto, 2012)
    The purpose of this study was to obtain information to support decision making in the development of successful teaching strategies and clinical placements among English-Language-Taught Degree Programmes (ELTDP) in faculties of healthcare in Finnish universities of applied sciences. This was achieved by descriptions and analysis of the experiences and conceptions of students and teachers. A methodological triangulation was used to conduct the study. In the first phase, descriptions of the students and the teachers experiences of teaching strategies and clinical placements were sought. Data were collected from general nursing and public health nursing teachers (n=18) and also from nursing students (n=27) through focus groups interview. The data were analyzed through thematic content analysis. In the second phase, a structured questionnaire based on the results of the first phase and relevant literature was developed to further investigate the students views. This instrument included items grouped as dimensions for teaching strategies (7 dimensions) and for clinical placements (5 dimensions). The quantitative data were collected from 283 general nursing, public health nursing and physiotherapy students. Statistical methods were used to analyze the data, which compared Finnish students experiences with Finnish students experiences. The findings of the first phase of the study suggest that both students and teachers alike perceived concreteness of instruction as important for ELTDP students learning. Similarly, both groups emphasized the value of the use of a variety of student centered methods to promote the learning of everyone in the culturally diverse student population. The clinical placements were perceived as challenging, due to international students lack of Finnish or Swedish speaking proficiency and also due to their negative experiences in the placements. The findings of the second phase revealed that all ELTDP students experiences of the dimensions of teaching strategies were mainly positive. The most positive experiences for all were with the cultural diversity in the learning community and with concreteness and practicality of theoretical instruction. The most negative experiences were about assessments. The international students felt less satisfied with their lives than did their Finnish peers. However, all students felt motivated to complete their studies. Despite the fact that the international students felt welcome on their placements, they were more likely than the Finnish students to have had the experience of an unsupportive clinical environment. Key words: cultural diversity, healthcare student, teaching strategies, clinical placements, ELTDP students, conceptions of students and teachers.