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  • Laas, Karin (Helsingin yliopisto, 2009)
    Rheumatoid arthritis (RA) and other chronic inflammatory joint diseases already begin to affect patients health-related quality of life (HRQoL) in the earliest phases of these diseases. In treatment of inflammatory joint diseases, the last two decades have seen new strategies and treatment options introduced. Treatment is started at an earlier phase; combinations of disease-modifying anti-rheumatic drugs (DMARDs) and corticosteroids are used; and in refractory cases new drugs such as tumour necrosis factor (TNF) inhibitors or other biologicals can be started. In patients with new referrals to the Department of Rheumatology of the Helsinki University Central Hospital, we evaluated the 15D and the Stanford Health Assessment Questionnaire (HAQ) results at baseline and approximately 8 months after their first visit. Altogether the analysis included 295 patients with various rheumatic diseases. The mean baseline 15D score (0.822, SD 0.114) was significantly lower than for the age-matched general population (0.903, SD 0.098). Patients with osteoarthritis (OA) and spondyloarthropathies (SPA) reported the poorest HRQoL. In patients with RA and reactive arthritis (ReA) the HRQoL improved in a statistically significant manner during the 8-month follow-up. In addition, a clinically important change appeared in patients with systemic rheumatic diseases. HAQ score improved significantly in patients with RA, arthralgia and fibromyalgia, and ReA. In a study of 97 RA patients treated either with etanercept or adalimumab, we assessed their HRQoL with the RAND 36-Item Health Survey 1.0 (RAND-36) questionnaire. We also analysed changes in clinical parameters and the HAQ. With etanercept and adalimumab, the values of all domains in the RAND-36 questionnaire increased during the first 3 months. The efficacy of each in improving HRQoL was statistically significant, and the drug effects were comparable. Compared to Finnish age- and sex-matched general population values, the HRQoL of the RA patients was significantly lower at baseline and, despite the improvement, remained lower also at follow-up. Our RA patients had long-standing and severe disease that can explain the low HRQoL also at follow-up. In a pharmacoeconomic study of patients treated with infliximab we evaluated medical and work disability costs for patients with chronic inflammatory joint disease during one year before and one year after institution of infliximab treatment. Clinical and economic data for 96 patients with different arthritis diagnoses showed, in all patients, significantly improved clinical and laboratory variables. However, the medical costs increased significantly during the second period by 12 015 (95% confidence interval, 6 496 to 18 076). Only a minimal decrease in work disability costs occurred mean decrease 130 (-1 268 to 1 072). In a study involving a switch from infliximab to etanercept, we investigated the clinical outcome in 49 patients with RA. Reasons for switching were in 42% failure to respond by American College of Rheumatology (ACR) 50% criteria; in 12% adverse event; and in 46% non-medical reasons although the patients had responded to infliximab. The Disease Activity Score with 28 joints examined (DAS28) allowed us to measure patients disease activity and compare outcome between groups based on the reason for switching. In the patients in whom infliximab was switched to etanercept for nonmedical reasons, etanercept continued to suppress disease activity effectively, and 1-year drug survival for etanercept was 77% (95% CI, 62 to 97). In patients in the infliximab failure and adverse event groups, DAS28 values improved significantly during etanercept therapy. However, the 1-year drug survival of etanercept was only 43% (95% CI, 26 to 70) and 50% (95% CI, 33 to 100), respectively. Although the HRQoL of patients with inflammatory joint diseases is significantly lower than that of the general population, use of early and aggressive treatment strategies including TNF-inhibitors can improve patients HRQoL effectively. Further research is needed in finding new treatment strategies for those patients who fail to respond or lose their response to TNF-inhibitors.
  • Kaukua, Jarmo (Helsingin yliopisto, 2004)
  • Haapamäki, Johanna (Helsingin yliopisto, 2011)
    Health-related quality of life (HRQoL) measurement has become an important outcome in treatment trials and in health policy decisions. HRQoL can be measured by using generic or disease-specific tools. Generic instruments can be used for comparing health status among patients in different health states and conditions but they do not focus specifically on the issues relevant in a particular disease. Disease-specific tools may be more responsive to changes within a specific condition. In earlier studies, impairment of HRQoL has been evident in patients with inflammatory bowel disease (IBD), especially when the disease is active. Data about the impact of comorbidity or demographic characteristics of the patients on HRQoL are partly controversial. This study, which comprised 2913 adult IBD patients, examined HRQoL using the disease-specific IBDQ and the general 15D instruments. The 15D scores of IBD patients were compared with scores of a gender and age matched general population sample. Frequency of IBD symptoms and arrangement of therapy were studied and compared with those of IBD patients in an earlier European study. Furthermore, data of other chronic diseases of the patients were obtained from the Social Insurance Institution s reimbursement register and comorbidity of IBD patients was compared with that of age and gender matched controls. --- Of the respondents, 37% reported that they suffered from disturbing IBD symptoms weekly. In 17% of the patients, the symptoms greatly affected the ability to enjoy leisure activities, and 14% stated that these symptoms greatly affected their capacity to work. Despite that, the great majority (93%) of patients expressed satisfaction with their current treatment, which exceeded the rate observed in the other European patients. The mean IBDQ score was 163, as the possible range is 32-224, and disease activity was strongly correlated with HRQoL. Older age, comorbid diseases, and female gender were also related to impairment of HRQoL. Lower HRQoL scores were seen also in newly-diagnosed patients and in those with a history of surgery, especially after stoma or ileal pouch-anal anastomosis (IPAA) operation. The range of 15D scores was 0.30-1.00, with mean of 0.87. As with the IBDQ, disease activity, older age and history of surgery were correlated with the score. Both the newly-diagnosed patients and patients with a long-lasting disease had lower scores than average even after adjusting for age. The 15D scores of IBD patients were significantly lower than those of the control group. A strong correlation was seen between the 15D and the IBDQ scores. Comorbidity with other chronic diseases was observed in 29% of IBD patients. Connective tissue diseases, chronic obstructive pulmonary diseases, pernicious anaemia, and coronary heart disease (CHD) were significantly increased in patients with IBD. Especially female IBD patients appeared to be at increased risk for CHD, and patients who reported weekly IBD symptoms had a higher risk for having other chronic diseases in addition to IBD. Comorbidity impaired HRQoL, as measured with both generic and disease-specific tools. In conclusion, HRQoL is impaired in IBD patients. An understanding of predictors of HRQoL will help to recognise patients who will need special support.
  • Nihtilä, Annamari (Helsingin yliopisto, 2014)
    A reform to Dental Care legislation in 2002 abolished age limits restricting adults use of public dental services in Finland. This Dental Reform aimed to increase equity by improving adults´ access to care and reducing cost barriers. The adult population´s increased demand for dental care put pressure on the Public Dental Service (PDS). The aim of this study was to compare heavy and low use of dental services in the PDS of Espoo in order to identify reasons for heavy use and to suggest improvements to care provision. This study is based on register data. All patients who had visited the PDS of Espoo in 2004 (n=63 850) were divided into two groups: children and adolescents and adults. Within each group, all patients who had made six or more dental visits to the PDS in 2004 were defined as heavy users of oral health services and all the patients who had had three or fewer visits as low users. A random sample of 320 adult patients and a 245 children and adolescent patients was drawn from each group. All adult heavy and low consumers of dental services identified in 2004, were followed for five years. Information on age, sex, number and types of visits, oral health status and treatment provided was collected from treatment records. Seven per cent of the children and adolescents in 2004 could be classified as heavy users and the main reasons of heavy use were high numbers of orthodontic treatment occasions provided by dentists and high numbers of decayed teeth in a small number of children. For adults, 10% were heavy users. A need for complicated treatment, dentists´ and dental hygienists´ lack of experience of adult dental care and lack of specialist resulted in high numbers of visits for these patients. The adult heavy users were older and had lower social status than low users. Of these baseline adult heavy users 11% persisted as chronic frequent users during 2005-2009. Typical for adult heavy use in the baseline and the follow-up study was a lack of proper examinations, poor quality of periodontal diagnosis, lack of preventive care, and a cycle of repetitive repair or replacement of restorations, often as emergency treatment. Fixed prosthetic treatment was seldom used in the PDS of Espoo. The PDS should seek to early identify possible heavy users and they should be offered a comprehensive approach to treatment and a responsible team of a dentist and dental hygienist. In order to manage adult dental health effectively, the PDS should encourage regular examinations, treatment plans and recall visits based on patients´ oral health and risk factors.
  • Koskenpato, Jari (Helsingin yliopisto, 2001)
  • Salomaa-Räsänen, Anniina (Helsingfors universitet, 2008)
    Helicobacter pylori (H. pylori) causes a life long infection on the gastric mucosa which can lead to peptic ulcers and premalignant and malignant conditions. The infection, mainly acquired in childhood, rarely resolves spontaneously. Timely eradication of H. pylori improves dramatically the prognosis of peptic ulcer disease and seems to prevent subsequent gastric malignancies. We started in the primary health care practice in Vammala, Finland, a unique population-based, voluntary 'screen-and-treat' H. pylori pilot study in 1994. In 1996 the study was extended to include all inhabitants aged 15 to 40 years and in 1997-2000 all inhabitants aged 15 and 45 years; the participitation rate was 75%. Altogether 4626 subjects were screened for H. pylori infection using serology. All infected ones were offered eradication therapy. The eradication rates were 82.2% per-protocol and 71.9% in intention-to-treat analysis among the 3326 15 to 40-year-old participants in 1996. H. pylori seroprevalence rates were calculated to have decreased from 12% to 4% among them. Differences between H. pylori antibody-positive and -negative subjects and risk factors for H. pylori infection were studied using a questionnaire. In multivariate analysis, crowding in the childhood household, low education of the mother, smoking and alcohol consumption, unfavourable housing conditions, and sick leave due to dyspepsia were associated with H. pylori infection. We determined in different age-groups the accuracy of H. pylori IgG and IgA antibody tests used in the 'screen-and-treat' programme, with special emphasis on the presence of atrophic gastritis. In 561 consecutive adult patients who underwent gastroscopy for clinical indications the IgG test was highly sensitive (99%) in all age groups. The specificity was 99% in subjects aged 15- 49, and high also in those aged 50-64 and those aged 65 or older (97% and 93%, respectively), when patients with atrophic gastritis were excluded. Both IgA and CagA antibody responses during H. pylori infection have been found to be associated with an increased risk of peptic ulcers and gastric malignancies. By reanalysing paired serum samples collected with two decade’s interval from 560 subjects we found that the increase in the prevalence of IgA antibodies with age was due not only to the birth cohort phenomenon and seroconverters, but also to increasing IgA antibody levels during infection. The change in the prevalence of CagA antibodies was studied by reanalysing sera collected from 408 subjects in 1973 and from 503 subjects in 1994. The proportion of subjects infected with CagA+ H. pylori strains had declined faster than that of subjects infected with CagA- H. pylori strains, while the overall prevalence of H. pylori had declined.
  • Koivisto, Tarmo (Helsingin yliopisto, 2008)
    Background: Helicobacter pylori infection is usually acquired in early childhood and is rarely resolved spontaneously. Eradication therapy is currently recommended virtually to all patients. While the first and second therapies are prescribed without knowing the antibiotic resistance of the bacteria, it is important to know the primary resistance in the population. Aim: This study evaluates the primary resistance of H. pylori among patients in primary health care throughout Finland, the efficacy of three eradication regimens, the symptomatic response to successful therapy, and the effect of smoking on gastric histology and humoral response in H. pylori-positive patients. Patients and methods: A total of 23 endoscopy referral centres located throughout Finland recruited 342 adult patients with positive rapid urease test results, who were referred to upper gastrointestinal endoscopy from primary health care. Gastric histology, H. pylori resistance and H. pylori serology were evaluated. The patients were randomized to receive a seven-day regimen, comprising 1) lansoprazole 30 mg b.d., amoxicillin 1 g b.d. and metronidazole 400 mg t.d. (LAM), 2) lansoprazole 30 mg b.d., amoxicillin 1 g b.d. and clarithromycin 500 mg b.d. (LAC) or 3) ranitidine bismuth citrate 400 mg b.d., metronidazole 400 mg t.d. and tetracycline 500 mg q.d. (RMT). The eradication results were assessed, using the 13C-urea breath test 4 weeks after therapy. The patients completed a symptom questionnaire before and a year after the therapy. Results: Primary resistance of H. pylori to metronidazole was 48% among women and 25% among men. In women, metronidazole resistance correlated with previous use of antibiotics for gynaecologic infections and alcohol consumption. Resistance rate to clarithromycin was only 2%. Intention-to-treat cure rates of LAM, LAC, and RMT were 78%, 91% and 81%. While in metronidazole-sensitive cases the cure rates with LAM, LAC and RMT were similar, in metronidazole resistance LAM and RMT were inferior to LAC (53%, 67% and 84%). Previous antibiotic therapies reduced the efficacy of LAC, to the level of RMT. Dyspeptic symptoms in the Gastrointestinal Symptoms Rating Scale (GSRS) were decreased by 30.5%. In logistic regression analysis, duodenal ulcer, gastric antral neutrophilic inflammation and age from 50 to 59 years independently predicted greater decrease in dyspeptic symptoms. In the gastric body, smokers had milder inflammation and less atrophy and in the antrum denser H. pylori load. Smokers also had lower IgG antibody titres against H. pylori and a smaller proportional decrease in antibodies after successful eradication. Smoking tripled the risk of duodenal ulcers. Conclusions: in Finland H. pylori resistance to clarithromycin is low, but metronidazole resistance among women is high making metronidazole-based therapies unfavourable. Thus, LAC is the best choice for first-line eradication therapy. The effect of eradication on dyspeptic symptoms was only modest. Smoking slows the progression of atrophy in the gastric body.
  • Gekas, Christos (Helsingin yliopisto, 2008)
    The continuous production of blood cells, a process termed hematopoiesis, is sustained throughout the lifetime of an individual by a relatively small population of cells known as hematopoietic stem cells (HSCs). HSCs are unique cells characterized by their ability to self-renew and give rise to all types of mature blood cells. Given their high proliferative potential, HSCs need to be tightly regulated on the cellular and molecular levels or could otherwise turn malignant. On the other hand, the tight regulatory control of HSC function also translates into difficulties in culturing and expanding HSCs in vitro. In fact, it is currently not possible to maintain or expand HSCs ex vivo without rapid loss of self-renewal. Increased knowledge of the unique features of important HSC niches and of key transcriptional regulatory programs that govern HSC behavior is thus needed. Additional insight in the mechanisms of stem cell formation could enable us to recapitulate the processes of HSC formation and self-renewal/expansion ex vivo with the ultimate goal of creating an unlimited supply of HSCs from e.g. human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPS) to be used in therapy. We thus asked: How are hematopoietic stem cells formed and in what cellular niches does this happen (Papers I, II)? What are the molecular mechanisms that govern hematopoietic stem cell development and differentiation (Papers III, IV)? Importantly, we could show that placenta is a major fetal hematopoietic niche that harbors a large number of HSCs during midgestation (Paper I)(Gekas et al., 2005). In order to address whether the HSCs found in placenta were formed there we utilized the Runx1-LacZ knock-in and Ncx1 knockout mouse models (Paper II). Importantly, we could show that HSCs emerge de novo in the placental vasculature in the absence of circulation (Rhodes et al., 2008). Furthermore, we could identify defined microenvironmental niches within the placenta with distinct roles in hematopoiesis: the large vessels of the chorioallantoic mesenchyme serve as sites of HSC generation whereas the placental labyrinth is a niche supporting HSC expansion (Rhodes et al., 2008). Overall, these studies illustrate the importance of distinct milieus in the emergence and subsequent maturation of HSCs. To ensure proper function of HSCs several regulatory mechanisms are in place. The microenvironment in which HSCs reside provides soluble factors and cell-cell interactions. In the cell-nucleus, these cell-extrinsic cues are interpreted in the context of cell-intrinsic developmental programs which are governed by transcription factors. An essential transcription factor for initiation of hematopoiesis is Scl/Tal1 (stem cell leukemia gene/T-cell acute leukemia gene 1). Loss of Scl results in early embryonic death and total lack of all blood cells, yet deactivation of Scl in the adult does not affect HSC function (Mikkola et al., 2003b. In order to define the temporal window of Scl requirement during fetal hematopoietic development, we deactivated Scl in all hematopoietic lineages shortly after hematopoietic specification in the embryo . Interestingly, maturation, expansion and function of fetal HSCs was unaffected, and, as in the adult, red blood cell and platelet differentiation was impaired (Paper III)(Schlaeger et al., 2005). These findings highlight that, once specified, the hematopoietic fate is stable even in the absence of Scl and is maintained through mechanisms that are distinct from those required for the initial fate choice. As the critical downstream targets of Scl remain unknown, we sought to identify and characterize target genes of Scl (Paper IV). We could identify transcription factor Mef2C (myocyte enhancer factor 2 C) as a novel direct target gene of Scl specifically in the megakaryocyte lineage which largely explains the megakaryocyte defect observed in Scl deficient mice. In addition, we observed an Scl-independent requirement of Mef2C in the B-cell compartment, as loss of Mef2C leads to accelerated B-cell aging (Gekas et al. Submitted). Taken together, these studies identify key extracellular microenvironments and intracellular transcriptional regulators that dictate different stages of HSC development, from emergence to lineage choice to aging.
  • Lakkisto, Päivi (Helsingin yliopisto, 2010)
    Myocardial infarction (MI) and heart failure are major causes of morbidity and mortality worldwide. Treatment of MI involves early restoration of blood flow to limit infarct size and preserve cardiac function. MI leads to left ventricular remodeling, which may eventually progress to heart failure, despite the established pharmacological treatment of the disease. To improve outcome of MI, new strategies for protecting the myocardium against ischemic injury and enhancing the recovery and repair of the infarcted heart are needed. Heme oxygenase-1 (HO-1) is a stress-responsive and cytoprotective enzyme catalyzing the degradation of heme into the biologically active reaction products biliverdin/bilirubin, carbon monoxide (CO) and free iron. HO-1 plays a key role in maintaining cellular homeostasis by its antiapoptotic, anti-inflammatory, antioxidative and proangiogenic properties. The present study aimed, first, at evaluating the role of HO-1 as a cardioprotective and prohealing enzyme in experimental rat models and at investigating the potential mechanisms mediating the beneficial effects of HO-1 in the heart. The second aim was to evaluate the role of HO-1 in 231 critically ill intensive care unit (ICU) patients by investigating the association of HO-1 polymorphisms and HO-1 plasma concentrations with illness severity, organ dysfunction and mortality throughout the study population and in the subgroup of cardiac patients. We observed in an experimental rat MI model, that HO-1 expression was induced in the infarcted rat hearts, especially in the infarct and infarct border areas. In addition, pre-emptive HO-1 induction and CO donor pretreatment promoted recovery and repair of the infarcted hearts by differential mechanisms. CO promoted vasculogenesis and formation of new cardiomyocytes by activating c-kit+ stem/progenitor cells via hypoxia-inducible factor 1 alpha, stromal cell-derived factor 1 alpha (SDF-1a) and vascular endothelial growth factor B, whereas HO-1 promoted angiogenesis possibly via SDF-1a. Furthermore, HO-1 protected the heart in the early phase of infarct healing by increasing survival and proliferation of cardiomyocytes. The antiapoptotic effect of HO-1 persisted in the late phases of infarct healing. HO-1 also modulated the production of extracellular matrix components and reduced perivascular fibrosis. Some of these beneficial effects of HO-1 were mediated by CO, e.g. the antiapoptotic effect. However, CO may also have adverse effects on the heart, since it increased the expression of extracellular matrix components. In isolated perfused rat hearts, HO-1 induction improved the recovery of postischemic cardiac function and abrogated reperfusion-induced ventricular fibrillation, possibly in part via connexin 43. We found that HO-1 plasma levels were increased in all critically ill patients, including cardiac patients, and were associated with the degree of organ dysfunction and disease severity. HO-1 plasma concentrations were also higher in ICU and hospital nonsurvivors than in survivors, and the maximum HO-1 concentration was an independent predictor of hospital mortality. Patients with the HO-1 -413T/GT(L)/+99C haplotype had lower HO-1 plasma concentrations and lower incidence of multiple organ dysfunction. However, HO-1 polymorphisms were not associated with ICU or hospital mortality. The present study shows that HO-1 is induced in response to stress in both experimental animal models and severely ill patients. HO-1 played an important role in the recovery and repair of infarcted rat hearts. HO-1 induction and CO donor pretreatment enhanced cardiac regeneration after MI, and HO-1 may protect against pathological left ventricular remodeling. Furthermore, HO-1 induction potentially may protect against I/R injury and cardiac dysfunction in isolated rat hearts. In critically ill ICU patients, HO-1 plasma levels correlate with the degree of organ dysfunction, disease severity, and mortality, suggesting that HO-1 may be useful as a marker of disease severity and in the assessment of outcome of critically ill patients.
  • Karhunen, Janne (Helsingin yliopisto, 2014)
    Sudden hemodynamic collapse after coronary artery bypass surgery is a major complication associated with high mortality and morbidity. There are many well-established risk stratification systems to assess the risk of mortality and morbidity after cardiac surgery. These risk scores, however, do not predict severe immediate postoperative complications such as sudden hemodynamic collapse. This study is based on analysis of patients who suffered from hemodynamic collapse early after coronary artery bypass surgery between 1988 and 1999 in Helsinki University Hospital. One matched control patient was selected for every study patient. Patients, who died, underwent a medico-legal autopsy and a rubber cast angiography to reveal possible surgical errors in myocardial revascularization. Patients still alive in 2009 were traced with respect to mortality data and a health-related quality of life questionnaire was sent to the patients and to the controls. In addition, a comparison was made between patients who suffered from postoperative hemodynamic collapse and patients who underwent a postoperative angiography due to persistent myocardial ischemia. Angiography was introduced in 2000 and this patient series was collected prospectively between 2000 and 2007. This thesis consists of four studies. The specific goals were to explore predictive factors of sudden hemodynamic collapse, to reveal the possible surgical errors that led to hemodynamic collapse and fatal outcome with the means of an autopsy, to find out the impact that postoperative angiography has on the incidence of hemodynamic collapse, and the rate of mortality, and morbidity of patients, and to investigate the quality of life of patients surviving hemodynamic collapse in comparison with an age- and sex-matched national reference population. The results suggest the following: Sudden hemodynamic collapse after CABG is a major complication with high mortality. Inadequate tissue perfusion, postoperative myocardial ischemia, and increased need for inotropic as well as mechanical support are predictive of hemodynamic collapse. Technical graft complications are a major underlying cause of postoperative hemodynamic collapse. Post-mortem angiography improves the accuracy of diagnostics of graft complications. The cause of death could be established in every case. Use of early postoperative angiography in case of hemodynamic compromise or myocardial ischemia reduces the rate of emergency reoperations and decreases morbidity and mortality. It also allows treatment with intravascular medication. Patients who survive hemodynamic collapse and emergency reoperations have a similar prognosis as matched control patients. Health-related quality of life that is also comparable with age- and sex-matched national reference population as long as 15 years postoperatively.
  • Varpula, Marjut (Helsingin yliopisto, 2007)
    Septic shock is a common killer in intensive care units (ICU). The most crucial issue concerning the outcome is the early and aggressive start of treatment aimed at normalization of hemodynamics and the early start of antibiotics during the very first hours. The optimal targets of hemodynamic treatment, or impact of hemodynamic treatment on survival after first resuscitation period are less known. The objective of this study was to evaluate different aspects of the hemodynamic pattern in septic shock with special attention to prediction of outcome. In particular components of early treatment and monitoring in the ICU were assessed. A total of 401 patients, 218 with septic shock and 192 with severe sepsis or septic shock were included in the study. The patients were treated in 24 Finnish ICUs during 1999-2005. 295 of the patients were included in the Finnish national epidemiologic Finnsepsis study. We found that the most important hemodynamic variables concerning the outcome were the mean arterial pressures (MAP) and lactate during the first six hours in ICU and the MAP and mixed venous oxygen saturation (SvO2) under 70% during first 48 hours. The MAP levels under 65 mmHg and SvO2 below 70% were the best predictive thresholds. Also the high central venous pressure (CVP) correlated to adverse outcome. We assessed the correlation and agreement of SvO2 and mean central venous oxygen saturation (ScvO2) in septic shock during first day in ICU. The mean SvO2 was below ScvO2 during early sepsis. Bias of difference was 4.2% (95% limits of agreement 8.1% to 16.5%) by Bland-Altman analysis. The difference between saturation values correlated significantly to cardiac index and oxygen delivery. Thus, the ScvO2 can not be used as a substitute of SvO2 in hemodynamic monitoring in ICU. Several biomarkers have been investigated for their ability to help in diagnosis or outcome prediction in sepsis. We assessed the predictive value of N-terminal pro brain natriuretic peptide (NT-proBNP) on mortality in severe sepsis or septic shock. The NT-proBNP levels were significantly higher in hospital nonsurvivors. The NT-proBNP 72 hrs after inclusion was independent predictor of hospital mortality. The acute cardiac load contributed to NTproBNP values at admission, but renal failure was the main confounding factor later. The accuracy of NT-proBNP, however, was not sufficient for clinical decision-making concerning the outcome prediction. The delays in start of treatment are associated to poorer prognosis in sepsis. We assessed how the early treatment guidelines were adopted, and what was the impact of early treatment on mortality in septic shock in Finland. We found that the early treatment was not optimal in Finnish hospitals and this reflected to mortality. A delayed initiation of antimicrobial agents was especially associated with unfavorable outcome.
  • Wilkman, Erika (Helsingin yliopisto, 2014)
    BACKGROUND Adequate blood circulation is necessary for tissue perfusion and oxygen supply. Derangements in perfusion due to circulatory failure may lead to end-organ failure without prompt and accurate restoration of circulation and perfusion, which is performed by targeting sufficient levels of preload, afterload, and cardiac contractility. Current international guidelines recommend early vigorous fluid resuscitation, restoration of mean arterial pressure (MAP) to ≥60-65 mmHg, when necessary by using vasopressor agents, and restoration of depressed cardiac contractility and output by inotrope treatment to improve survival and avoid end-organ failure. However, evidence for the beneficial impact of inotrope use in septic shock, hemodynamic targets for resuscitation in severe acute pancreatitis (SAP), or optimal blood pressure for prevention of septic acute kidney injury is rather limited. Furthermore, feasible means of assessing fluid responsiveness to prevent excessive fluid resuscitation are warranted. The objective of this study was to evaluate different hemodynamic variables in addition to vasopressor and inotrope treatment during the early phases of severe sepsis, septic shock, and SAP and their association with development of end-organ failure and outcome. We also sought to find relevant hemodynamic parameters for assessing fluid responsiveness during early resuscitation of septic shock. PATIENTS A total of 1022 patients, 440 with septic shock, 159 with SAP, and 423 with severe sepsis, were included in the study. All patients were treated in the ICUs of Helsinki University Hospital during 2005-2012, except for the 423 patients with severe sepsis, who were treated in 13 different Finnish ICUs during 2011-2012. MAIN RESULTS Of patients with septic shock, 44.3% received inotrope treatment during the first 24 hours in the ICU, the majority of these patients receiving dobutamine (90.3%). The mortality of inotrope receivers was significantly higher than that of non-receivers (42.5% vs. 23.9%). Patients who received inotropes were generally more severely ill and received higher doses of norepinephrine. The use of inotropes in these patients was independently associated with worse outcome, also after adjustment with propensity score. In patients with severe sepsis and SAP, the use of inotropes was less frequent, 16.0% and 16.4%, respectively. Vasopressors, most often norepinephrine, were administered to the majority of patients with severe sepsis, SAP, and septic shock. The highest dose of norepinephrine during the first day in ICU was associated with worse outcome. Lower MAP, higher central venous pressure (CVP), and lower cardiac index (CI), but not higher heart rate (HR), were associated with 90-day mortality in patients with SAP. Decreases in MAP and systolic arterial pressure were the best predictors of fluid responsiveness in 20 mechanically ventilated patients with septic shock during a temporary elevation of positive end-expiratory pressure (PEEP) from 10 to 20 cm H2O. A decrease of less than 8% ruled out fluid responsiveness, with a negative predictive value of 100%. The time-adjusted MAP during the first 24 hours in the ICU of patients developing acute kidney injury (AKI) during the first five days in the ICU was significantly lower than that of patients not developing AKI (74.4 mmHg vs. 78.6 mmHg). The best cut-off value for time-adjusted MAP was 72.7 mmHg. Lower time-adjusted MAP or alternatively time-adjusted MAP below 73 mmHg was independently associated with progression of AKI. CONCLUSIONS Inotropes are frequently used in patients with septic shock. In severe sepsis and SAP, inotrope use is less frequent. The vast majority of patients received vasopressor treatment. Norepinephrine was the vasopressor of choice in nearly all patients. Use of inotropes and the highest vasopressor dose during the first day in ICU were significantly associated with 90-day mortality. Although inotropes may have beneficial effects in patients with septic shock, by increasing cardiac output and perfusion, they might also have adverse effects that eventually lead to higher mortality. Although vigorous fluid resuscitation is advocated in the early treatment of SAP to maintain sufficient tissue perfusion, our study showed that overzealous resuscitation might be harmful, reflected by the association of higher CVP with worse outcome. To avoid overhydration during fluid resuscitation of patients with septic shock, a lack of a decrease in MAP during elevation of PEEP from 10 to 20 cm H2O may be used as an accessory means of assessing fluid responsiveness. Lower time-adjusted MAP in patients with severe sepsis is associated with progression of AKI. Higher targets of MAP may be indicated for ensuring adequate perfusion of the kidney in this patient group.  
  • Lehtovirta, Mikko (Helsingin yliopisto, 2014)
    Disturbances in insulin sensitivity and insulin secretion precede the manifestation of type 2 diabetes. Both genes and environment contribute to the diabetes risk. Heritability indicates the proportion to which genotype determines the variability of a trait, such as for example blood glucose concentration. The current work was done for the Hjelt institute and for the Finnish institute of Molecular Medicine (FiMM) in the University of Helsinki. Heritability of insulin sensitivity, insulin secretion and traits associated with type 2 diabetes were estimated by means of twin and family studies. The twins belonged to the Finnish Twin Cohort Study of the University of Helsinki and the families participated in the Botnia study, a project on type 2 diabetes genetics. The collecting of the material was made between the years 1992 - 2004. Insulin sensitivity was measured by means of hyperinsulinaemic euglycaemic clamp technique. Insulin secretion was measured both via oral (OGTT) and intravenous (IVGTT) glucose tolerance tests. The heritability of body mass index (BMI) and type 2 diabetes were estimated in a follow-up study of twins. Furthermore, heritability estimates of several glucose metabolism and insulin sensitivity related traits were obtained by examining Botnia study families where at least two family members had type 2 diabetes. Altogether 66 monozygotic (MZ) and 85 dizygotic (DZ) twin pairs underwent OGTT. A subset of the pairs participated also in IVGTT- and clamp studies. The follow-up study was based on information that was received from 10400 twin pairs during a maximum of 28 years of follow-up. From the Botnia-study, 5810 adults from 942 families were chosen: 1707 of them had type 2 diabetes. The average family size was 6,17. On the basis of the metabolic studies, it was concluded that the genotype determines the insulin secretion's early phase, which begins immediately after the ingestion or infusion of glucose. The heritability of this trait varied between 55% and 76%. The majority of variation in insulin sensitivity, instead, seemed to be due to non-hereditary factors, as the heritability of insulin sensitivity was only 37%. In the follow-up study, 6.3% of male and 5.1% of female twins got type 2 diabetes. BMI calculated on the basis of the data recorded at the start of the follow-up, predicted future diabetes well. On average, the hazard ratio for type 2 diabetes was 1,22 per each BMI unit and the risk began to increase already from the BMI-value of 20kg/m2. The hazard ratios for type 2 diabetes in normal weight, overweight, obese and morbidly obese twins were 0.59, 2.96, 6.80 and 13.64, respectively. When BMI and type 2 diabetes were modelled together, the heritability of BMI in men was 75%, and 71% in women. Correspondingly, the heritability of type 2 diabetes was 73% in men and 64% in women, respectively. The genetic factors influencing BMI explained only 16% of the risk for type 2 diabetes among men and 21% of the risk among women. In the Botnia study, the highest heritability estimate for type 2 diabetes, 69%, was observed among individuals aged 35 to 60 years. The heritability of the early phase of insulin secretion varied between 41% (all subjects) and 50% (non-diabetic subjects). The heritability of insulin sensitivity was the same as among twins, from 37% to 40%. Among diabetes-related traits, the highest heritability estimates were obtained for lean body mass (53% to 65%), serum HDL cholesterol concentration (52% to 61%) and suppression of free fatty acids during OGTT (63% to 76%). The variation of all insulin sensitivity and insulin secretion -related traits were smaller within than between families. It is stated as a summary of this doctoral thesis that the risk for type 2 diabetes seems to be an inherited trait. A relatively small share in this risk, on the other hand, seems to be due to genes which influence BMI. Finally, the early phase of the pancreatic insulin secretion appears to be an aspect of metabolism that encompasses promising phenotypes for genomic studies.
  • Kallio-Laine, Katariina (Helsingin yliopisto, 2009)
    Background: Aims of the study were: (i) to characterise the clinical picture, immunological features and changes in brain morphology and function in patients with widespread unilateral pain and HSV-infections, and (ii) to analyse the prevalence, clinical symptoms and immunological predisposing factors of HSV-2 induced recurrent lymphocytic meningitis (RLM) in Southern Finland. Patients and methods: Patients for the studies were recruited from the Pain Clinic, and from the Department of Neurology, at Helsinki University Central Hospital. Plasma concentrations of IgM, IgA, IgG, and IgG1-4, and serum concentrations of C3, C4 were measured. Serological anti-HSV-1 and -2 antibody status was tested. C4 genotyping, HLA-A, HLA-B and HLA-DRB1 typing, MBL2 genotyping, and IgG1 and IgG3 allotyping (Gm) were performed. Clinical neurological examination, quantitative sensory testing, skin biopsy, and functional magnetic resonance imaging were also performed. Results: HSV probably has a role in the generation of a pathological pain state. Low serum IgG1 and IgG3 levels, made the patients vulnerable for recurring HSV infections. Both functional and structural changes were observed in the brain pain-processing areas in the patients: they had less pain-related activity in the insular cortices bilaterally, in the anterior cingular cortex (ACC), and in the thalamus, and the gray matter density was lower in the ACC, in the frontal and prefrontal cortices. In the meningitis studies it was shown that RLM is more common and less benign than previously reported, and that neuropathic pain is frequently present both during and after meningitis episodes. HLA-DRB1*01, HLA-B*27, and low IgG1 levels are predisposing factors for RLM. Conclusions: Patients are vulnerable to recurrent HSV infections because of subtle immunological abnormalities. HSV causes diverse clinical manifestations. First, the herpes simplex virus, or the inflammatory process triggered by it, may cause pathological widespread pain probably by activating glial cells in the CNS. In these patients, signs of alterations in the brain pain-processing areas can be demonstrated by functional brain imaging methods. Secondly, HSV-2 induced RLM is a rare complication of HSV-2 virus. The predisposing factors include low IgG1 subclass levels, HLA-DRB1*01 and HLA –B*27 genotypes. Neuropathic pain is frequently associated with RLM.
  • Badeau, Robert (Helsingin yliopisto, 2009)
    Reverse cholesterol transport (RCT) is an important function of high-density lipoproteins (HDL) in the protection of atherosclerosis. RCT is the process by which HDL stimulates cholesterol removal from peripheral cells and transports it to the liver for excretion. Premenopausal women have a reduced risk for atherosclerosis compared to age-matched men and there exists a positive correlation for serum 17β-estradiol (E2) and HDL levels in premenopausal women supporting the role of E2 in atherosclerosis prevention. In premenopausal women, E2 associates with HDL as E2 fatty acyl esters. Discovery of the cellular targets, metabolism, and assessment of the macrophage cholesterol efflux potential of these HDL-associated E2 fatty acyl esters were the major objectives of this thesis (study I, III, and IV). Soy phytoestrogens, which are related to E2 in both structure and function, have been proposed to be protective against atherosclerosis but the evidence to support these claims is conflicting. Therefore, another objective of this thesis was to assess the ability of serum from postmenopausal women, treated with isoflavone supplements (compared to placebo), to promote macrophage cholesterol efflux (study II). The scope of this thesis was to cover the roles that HDL-associated E2 fatty acyl esters have in the cellular aspects of RCT and to determine if soy isoflavones can also influence RCT mechanisms. SR-BI was a pivotal cellular receptor, responsible for hepatic and macrophage uptake and macrophage cholesterol efflux potential of HDL-associated E2 fatty acyl esters. Functional SR-BI was also critical for proper LCAT esterification activity which could impact HDL-associated E2 fatty acyl ester assembly and its function. In hepatic cells, LDL receptors also contributed to HDL-associated E2 fatty acyl esters uptake and in macrophage cells, estrogen receptors (ERs) were necessary for both HDL-associated E2 ester-specific uptake and cholesterol efflux potential. HDL-containing E2 fatty acyl esters (E2-FAE) stimulated enhanced cholesterol efflux compared to male HDL (which are deficient in E2) demonstrating the importance of the E2 ester in this process. To support this, premenopausal female HDL, which naturally contains E2, showed greater macrophage cholesterol efflux compared to males. Additionally, hepatic and macrophage cells hydrolyzed the HDL-associated E2 fatty acyl ester into unesterified E2. This could have important biological ramifications because E2, not the esterified form, has potent cellular effects which may influence RCT mechanisms. Lastly, soy isoflavone supplementation in postmenopausal women did not modulate ABCA1-specific macrophage cholesterol efflux but did increase production of plasma pre-β HDL levels, a subclass of HDL. Therefore, the impact of isoflavones on RCT and cardiovascular health needs to be further investigated. Taken as a whole, HDL-associated E2 fatty acyl esters from premenopausal women and soy phytoestrogen treatment in postmenopausal women may be important factors that increase the efficiency of RCT through cellular lipoprotein-related processes and may have direct implications on the cardiovascular health of women.
  • Arvela, Eva (Helsingin yliopisto, 2011)
    The main purpose of revascularization procedures for critical limb ischaemia (CLI) is to preserve the leg and sustain the patient s ambulatory status. Other goals are ischaemic pain relief and healing of ischaemic ulcers. Patients with CLI are usually old and have several comorbidities affecting the outcome. Revascularization for CLI is meaningless unless both life and limb are preserved. Therefore, the knowledge of both patient- and bypass-related risk factors is of paramount importance in clinical decision-making, patient selection and resource allocation. The aim of this study was to identify patient- and graft-related predictors of impaired outcome after infrainguinal bypass for CLI. The purpose was to assess the outcome of high-risk patients undergoing infrainguinal bypass and to evaluate the usefulness of specific risk scoring methods. The results of bypasses in the absence of optimal vein graft material were also evaluated, and the feasibility of the new method of scaffolding suboptimal vein grafts was assessed. The results of this study showed that renal insufficiency - not only renal failure but also moderate impairment in renal function - seems to be a significant risk factor for both limb loss and death after infrainguinal bypass in patients with CLI. Low estimated GFR (PIENEMPI KUIN 30 ml/min/1.73 m2) is a strong independent marker of poor prognosis. Furthermore, estimated GFR is a more accurate predictor of survival and leg salvage after infrainguinal bypass in CLI patients than serum creatinine level alone. We also found out that the life expectancy of octogenarians with CLI is short. In this patient group endovascular revascularization is associated with a better outcome than bypass in terms of survival, leg salvage and amputation-free survival especially in presence of coronary artery disease. This study was the first one to demonstrate that Finnvasc and modified Prevent III risk scoring methods both predict the long-term outcome of patients undergoing both surgical and endovascular infrainguinal revascularization for CLI. Both risk scoring methods are easy to use and might be helpful in clinical practice as an aid in preoperative patient selection and decision-making. Similarly than in previous studies, we found out that a single-segment great saphenous vein graft is superior to any other autologous vein graft in terms of mid-term patency and leg salvage. However, if optimal vein graft is lacking, arm vein conduits are superior to prosthetic grafts especially in infrapopliteal bypasses for CLI. We studied also the new method of scaffolding suboptimal quality vein grafts and found out that this method may enable the use of vein grafts of compromised quality otherwise unsuitable for bypass grafting. The remarkable finding was that patients with the combination of high operative risk due to severe comorbidities and risk graft have extremely poor survival, suggesting that only relatively fit patients should undergo complex bypasses with risk grafts. The results of this study can be used in clinical practice as an aid in preoperative patient selection and decision-making. In the future, the need of vascular surgery will increase significantly as the elderly and diabetic population increases, which emphasises the importance of focusing on those patients that will gain benefit from infrainguinal bypass. Therefore, the individual risk of the patient, ambulatory status, outcome expectations, the risk of bypass procedure as well as technical factors such as the suitability of outflow anatomy and the available vein material should all be assessed and taken into consideration when deciding on the best revascularization strategy.
  • Almangush, Alhadi (Helsingin yliopisto, 2015)
    Histopathological predictors of early stage oral tongue cancer Oral tongue cancer constitutes the majority of malignancies of the oral cavity. In Finland during 2013, the age-adjusted incidence rates of oral tongue cancer were 1.7 per 100,000 in males and 0.8 per 100,000 in females. Staging of the clinical status of tumor size, lymph node, and metastasis (cTNM staging) is a widely accepted system for classification of many cancers including oral squamous cell carcinoma (OSCC). However, this staging system failed to prognosticate the outcome of early stage oral tongue squamous cell carcinoma (OTSCC). Numerous studies designed to introduce prognostic parameters and/or models to complement the insufficiency of cTNM staging and to predict the patient outcome have been carried out. Many of these prognostic models (or systems) were based on histopathologic parameters. However, all of the previously introduced models showed little or no predictive power in early stage (cT1-2N0) OTSCC. Thus, the identification of markers that predict the outcome of patients with early stage OTSCC is still necessary in order to apply effective individualized treatment. In this international collaborative study, we have examined the prognostic impact of several predictive factors in large patient cohorts from 7 institutions located in 3 geographic regions (Finland, Brazil, and USA). Moreover, we have introduced a new simple predictive model (BD score) for histopathologic classification and prognostication of early OTSCC. We suggest that this model could possibly be easily applied during the surgical resection, so patients with aggressive OTSCC could benefit from elective neck dissection (END) during the same procedure. This model could offer a step forward toward the personalized management of OTSCC. However, additional validation in different patient cohorts is still required.