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  • Pelkonen, Tuula (Helsingin yliopisto, 2011)
    Background Acute bacterial meningitis (BM) continues to be an important cause of childhood mortality and morbidity, especially in developing countries. Prognostic scales and the identification of risk factors for adverse outcome both aid in assessing disease severity. New antimicrobial agents or adjunctive treatments - except for oral glycerol - have essentially failed to improve BM prognosis. A retrospective observational analysis found paracetamol beneficial in adult bacteraemic patients, and some experts recommend slow β-lactam infusion. We examined these treatments in a prospective, double-blind, placebo-controlled clinical trial. Patients and methods A retrospective analysis included 555 children treated for BM in 2004 in the infectious disease ward of the Paediatric Hospital of Luanda, Angola. Our prospective study randomised 723 children into four groups, to receive a combination of cefotaxime infusion or boluses every 6 hours for the first 24 hours and oral paracetamol or placebo for 48 hours. The primary endpoints were 1) death or severe neurological sequelae (SeNeSe), and 2) deafness. Results In the retrospective study, the mortality of children with blood transfusion was 23% (30 of 128) vs. without blood transfusion 39% (109 of 282; p=0.004). In the prospective study, 272 (38%) of the children died. Of those 451 surviving, 68 (15%) showed SeNeSe, and 12% (45 of 374) were deaf. Whereas no difference between treatment groups was observable in primary endpoints, the early mortality in the infusion-paracetamol group was lower, with the difference (Fisher s exact test) from the other groups at 24, 48, and 72 hours being significant (p=0.041, 0.0005, and 0.005, respectively). Prognostic factors for adverse outcomes were impaired consciousness, dyspnoea, seizures, delayed presentation, and absence of electricity at home (Simple Luanda Scale, SLS); the Bayesian Luanda Scale (BLS) also included abnormally low or high blood glucose. Conclusions New studies concerning the possible beneficial effect of blood transfusion, and concerning longer treatment with cefotaxime infusion and oral paracetamol, and a study to validate our simple prognostic scales are warranted.
  • Suvisaari, Jaana (Helsingin yliopisto, 1999)
  • Nisula, Sara (Helsingin yliopisto, 2014)
    Acute kidney injury (AKI) is a syndrome encompassing kidney damage from mild injury to total loss of function that seriously disturbs the homeostasis of fluid and electrolyte balances. The objectives of this study were to evaluate the incidence, risk factors, and outcome of acute kidney injury in adult intensive care unit (ICU) patients in Finland, and to test the ability of two new biomarkers to predict AKI, renal replacement therapy (RRT), and 90-day mortality in ICU patients. A prospective, observational FINNAKI-study was conducted in 17 Finnish ICUs and all admitted patients were screened for eligibility during the study period of five months (2011-2012). All adult emergency admissions and elective admissions with an expected stay over 24 hours were included. AKI was defined with the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. Study I included all patients in the FINNAKI study and evaluated the incidence and risk factors for AKI and reported the 90-day mortality of patients with AKI. Of the 2901 patients 1141 (39%) developed AKI during the screening period of five days. The proportions of patients in the different stages of AKI were 499 (17%) in stage 1, 232 (8%) in stage 2, and 410 (14%) in stage 3. RRT was initiated for 272 (9%) patients. The population-based incidence of AKI was 746 per million adults per year. Patients that developed AKI were older and more severely ill, and had more chronic comorbidities than patients without AKI. Hypovolaemia prior to ICU admission, administration of diuretics or colloids (HES or gelatin) prior to ICU admission, and chronic kidney disease were independent risk factors for AKI. Of the 1141 AKI patients, 385 (34%) died within 90-days. In study II urine neutrophil gelatinase-associated lipocalin (NGAL) was measured from 1042 patients. NGAL predicted AKI with an AUC (95% CI) of 0.733 (0.701 0.765), RRT with an AUC (95% CI) of 0.839 (0.797 0.880), and 90-day mortality with an AUC (95% CI) of 0.634 (0.593 0.675). In Study III urine interleukin-18 (IL-18) was analysed from 1439 patients. IL-18 predicted the development of AKI with an AUC (95%CI) of 0.586 (0.546 - 0.627), initiation of RRT with an AUC (95% CI) of 0.655 (0.572 - 0.739), and 90-day mortality with an AUC (95% CI) of 0.536 (0.497 - 0.574). Study IV included 1568 patients and evaluated the 6-month mortality and the survivors health-related quality of life (HRQol) at ICU admission and six-months later with the EQ-5D questionnaire. The EQ-5D index for AKI patients at six-months (0.676) was lower than for the age- and sex-matched general population (0.826) but equal to that of patients without AKI (0.690). There was no significant change in the EQ-5D over six-months for either patient group. Despite their measured lower HRQol, AKI patients evaluated their quality of life to be as good as that of the age- and sex-matched general population at six-months after the ICU treatment with the EQ-5D visual analogue scale. Of the 635 AKI patients in this study, 224 (35%) died within 6-months. Incidence of AKI among critically ill patients was high. Hypovolaemia, diuretics, and colloids prior to ICU admission were independently associated with the development of AKI. In this population, urine NGAL was statistically associated with the need to initiate RRT, but the transformation of this result into clinical practice is complicated. Urine NGAL lacks power to predict AKI or 90-day mortality. Urine IL-18 has no adequate power to predict AKI, RRT, or 90-Day mortality in critically ill adult patients. AKI was associated with significantly increased 90-day and 6-month mortality. The HRQol of all ICU patients was lower than that of the age- and sex-matched general population already before ICU treatment. This HRQol did not change during critical illness or during a six-month follow up. Despite their lower HRQol, AKI patients felt their health was equal to that of the general population.
  • Linko, Rita (Helsingin yliopisto, 2012)
    Acute respiratory failure (ARF) is the most common organ failure in critically ill patients. Up to 74% of patients in intensive care units (ICUs) need some kind of ventilatory support. Additional organ failures are associated with higher mortality. High morbidity and mortality together with increased cost of mechanical ventilation, necessitates assessment of long-term outcome, and an analysis of cost-effectiveness. The aim of this study was to evaluate the incidence, treatment, and outcome of patients suffering from overall ARF, and a subset suffering from pandemic influenza A(H1N1) virus infection, in Finnish ICUs. The predictive value of serum zinc in organ failure and mortality was studied in ARF patients. One-year outcome for ARF was assessed. Health related quality of life (HRQOL), quality-adjusted life years (QALYs) for one-year survivors, and cost for one QALY, was estimated. A total of 958 patients from 25 Finnish ICUs needed ventilatory support for more than 6 hours during an 8-week period in 2007. Serum zinc level was assessd in 551 patients. A total of 132 H1N1 patients were assessed for incidence, treatment, and short-term outcome during an outbreak between 11 October and 31 December 2009. The incidence of ARF, and acute respiratory distress syndrome (ARDS) in the adult population were 149.5/100,000 and 5.0/100,000 per year, respectively. Median tidal volume per predicted body weight was 8.7 ml/kg and airway pressure was 19 cmH2O. The 90-day mortality of ARF was 31%, and one-year mortality was 35%. The incidence of H1N1 was 24.7 per million inhabitants. Corticosteroids were used frequently and their use was not associated with mortality in these patients. Rescue therapies, except prone positioning, were rarely used. Hospital mortality of H1N1 patients was 8%. The level of serum zinc decreased with increased severity of cardiovascular organ failure, but was not associated with 30-day mortality. HRQOL at one year after ARF was lower than population values of similar age and gender. The mean estimated cost for a hospital survivor was 20,739. The mean predicted lifetime QALYs were 11.3, and cost for one QALY for all ARF patients was 1,391. This study showed that the incidence of ARF was higher, while the incidence of ARDS was lower in Finland than reported from other countries. Tidal volumes were higher than recommended in the concept of lung protective ventilation. The short- and long term mortality was low. The incidence of H1N1 was similar to that previously reported. Corticosteroid treatment was frequently used. Hospital mortality of H1N1 was 8%. Serum zinc level was not useful in predicting 30-day mortality. Cost per hospital survivor, and lifetime cost-utility was reasonable.
  • Seikku, Paula (Helsingin yliopisto, 2008)
    Pediatric renal transplantation (TX) has evolved greatly during the past few decades, and today TX is considered the standard care for children with end-stage renal disease. In Finland, 191 children had received renal transplants by October 2007, and 42% of them have already reached adulthood. Improvements in treatment of end-stage renal disease, surgical techniques, intensive care medicine, and in immunosuppressive therapy have paved the way to the current highly successful outcomes of pediatric transplantation. In children, the transplanted graft should last for decades, and normal growth and development should be guaranteed. These objectives set considerable requirements in optimizing and fine-tuning the post-operative therapy. Careful optimization of immunosuppressive therapy is crucial in protecting the graft against rejection, but also in protecting the patient against adverse effects of the medication. In the present study, the results of a retrospective investigation into individualized dosing of immunosuppresive medication, based on pharmacokinetic profiles, therapeutic drug monitoring, graft function and histology studies, and glucocorticoid biological activity determinations, are reported. Subgroups of a total of 178 patients, who received renal transplants in 1988 2006 were included in the study. The mean age at TX was 6.5 years, and approximately 26% of the patients were <2 years of age. The most common diagnosis leading to renal TX was congenital nephrosis of the Finnish type (NPHS1). Pediatric patients in Finland receive standard triple immunosuppression consisting of cyclosporine A (CsA), methylprednisolone (MP) and azathioprine (AZA) after renal TX. Optimal dosing of these agents is important to prevent rejections and preserve graft function in one hand, and to avoid the potentially serious adverse effects on the other hand. CsA has a narrow therapeutic window and individually variable pharmacokinetics. Therapeutic monitoring of CsA is, therefore, mandatory. Traditionally, CsA monitoring has been based on pre-dose trough levels (C0), but recent pharmacokinetic and clinical studies have revealed that the immunosuppressive effect may be related to diurnal CsA exposure and blood CsA concentration 0-4 hours after dosing. The two-hour post-dose concentration (C2) has proved a reliable surrogate marker of CsA exposure. Individual starting doses of CsA were analyzed in 65 patients. A recommended dose based on a pre-TX pharmacokinetic study was calculated for each patient by the pre-TX protocol. The predicted dose was clearly higher in the youngest children than in the older ones (22.9±10.4 and 10.5±5.1 mg/kg/d in patients <2 and >8 years of age, respectively). The actually administered oral doses of CsA were collected for three weeks after TX and compared to the pharmacokinetically predicted dose. After the TX, dosing of CsA was adjusted according to clinical parameters and blood CsA trough concentration. The pharmacokinetically predicted dose and patient age were the two significant parameters explaining post-TX doses of CsA. Accordingly, young children received significantly higher oral doses of CsA than the older ones. The correlation to the actually administered doses after TX was best in those patients, who had a predicted dose clearly higher or lower (> ±25%) than the average in their age-group. Due to the great individual variation in pharmacokinetics standardized dosing of CsA (based on body mass or surface area) may not be adequate. Pre-Tx profiles are helpful in determining suitable initial CsA doses. CsA monitoring based on trough and C2 concentrations was analyzed in 47 patients, who received renal transplants in 2001 2006. C0, C2 and experienced acute rejections were collected during the post-TX hospitalization, and also three months after TX when the first protocol core biopsy was obtained. The patients who remained rejection free had slightly higher C2 concentrations, especially very early after TX. However, after the first two weeks also the trough level was higher in the rejection-free patients than in those with acute rejections. Three months after TX the trough level was higher in patients with normal histology than in those with rejection changes in the routine biopsy. Monitoring of both the trough level and C2 may thus be warranted to guarantee sufficient peak concentration and baseline immunosuppression on one hand and to avoid over-exposure on the other hand. Controlling of rejection in the early months after transplantation is crucial as it may contribute to the development of long-term allograft nephropathy. Recently, it has become evident that immunoactivation fulfilling the histological criteria of acute rejection is possible in a well functioning graft with no clinical sings or laboratory perturbations. The influence of treatment of subclinical rejection, diagnosed in 3-month protocol biopsy, to graft function and histology 18 months after TX was analyzed in 22 patients and compared to 35 historical control patients. The incidence of subclinical rejection at three months was 43%, and the patients received a standard rejection treatment (a course of increased MP) and/or increased baseline immunosuppression, depending on the severity of rejection and graft function. Glomerular filtration rate (GFR) at 18 months was significantly better in the patients who were screened and treated for subclinical rejection in comparison to the historical patients (86.7±22.5 vs. 67.9±31.9 ml/min/1.73m2, respectively). The improvement was most remarkable in the youngest (<2 years) age group (94.1±11.0 vs. 67.9±26.8 ml/min/1.73m2). Histological findings of chronic allograft nephropathy were also more common in the historical patients in the 18-month protocol biopsy. All pediatric renal TX patients receive MP as a part of the baseline immunosuppression. Although the maintenance dose of MP is very low in the majority of the patients, the well-known steroid-related adverse affects are not uncommon. It has been shown in a previous study in Finnish pediatric TX patients that steroid exposure, measured as area under concentration-time curve (AUC), rather than the dose correlates with the adverse effects. In the present study, MP AUC was measured in sixteen stable maintenance patients, and a correlation with excess weight gain during 12 months after TX as well as with height deficit was found. A novel bioassay measuring the activation of glucocorticoid receptor dependent transcription cascade was also employed to assess the biological effect of MP. Glucocorticoid bioactivity was found to be related to the adverse effects, although the relationship was not as apparent as that with serum MP concentration. The findings in this study support individualized monitoring and adjustment of immunosuppression based on pharmacokinetics, graft function and histology. Pharmacokinetic profiles are helpful in estimating drug exposure and thus identifying the patients who might be at risk for excessive or insufficient immunosuppression. Individualized doses and monitoring of blood concentrations should definitely be employed with CsA, but possibly also with steroids. As an alternative to complete steroid withdrawal, individualized dosing based on drug exposure monitoring might help in avoiding the adverse effects. Early screening and treatment of subclinical immunoactivation is beneficial as it improves the prospects of good long-term graft function.
  • Lepäntalo, Aino (Helsingin yliopisto, 2007)
    Antiplatelet medication is known to decrease adverse effects in patients with atherothrombotic disease. However, despite ongoing antiplatelet medication considerable number of patients suffer from atherothrombotic events. The aims of the study were 1) to evaluate the individual variability in platelet functions and compare the usability of different methods in detecting it, 2) to assess variability in efficacy of antiplatelet medication with aspirin (acetylsalicylic acid) or the combination of aspirin and clopidogrel and 3) to investigate the main genetic and clinical variables as well as potential underlying mechanisms of variability in efficacy of antiplatelet medication. In comparisons of different platelet function tests in 19 healthy individuals PFA-100® correlated with traditional methods of measuring platelet function and was thus considered appropriate for testing individual variability in platelet activity. Efficacy of ongoing 100mg aspirin daily was studied in 101 patients with coronary artery disease (CAD). Aspirin response was measured with arachidonic acid (AA)-induced platelet aggregation, which reflects cyclo-oxygenase (COX)-1 dependent thromboxane (Tx) A2 formation, and PFA-100®, which evaluates platelet activation under high shear stress in the presence of collagen and epinephrine. Five percent of patients failed to show inhibition of AA-aggregation and 21% of patients had normal PFA-100® results despite aspirin and were thus considered non-responders to aspirin. Interestingly, the two methods of assessing aspirin efficacy, platelet aggregation and PFA-100®, detected different populations as being aspirin non-responders. It could be postulated that PFA-100® actually measures enhanced platelet function, which is not directly associated with TxA2 inhibition exerted by aspirin. Clopidogrel efficacy was assessed in 50 patients who received a 300mg loading dose of clopidogrel 2.5 h prior to percutaneous coronary intervention (PCI) and in 51 patients who were given a loading dose of 300mg combined with a five day treatment of 75mg clopidogrel daily mimicking ongoing treatment. Clopidogrel response was assessed with ADP-induced aggregations, due to its mechanism of action as an inhibitor of ADP-induced activation. When patients received only a loading dose of clopidogrel prior to PCI, 40% did not gain measurable inhibition of their ADP-induced platelet activity (inhibition of 10% or less). Prolongation of treatment so that all patients had reached a plateau of inhibition exerted by clopidogrel, decreased the incidence of non-responders to 20%. Polymorphisms of COX-1 and GP VI, as well as diabetes and female gender, were associated with decreased in vitro aspirin efficacy. Diabetes also impaired the in vitro efficacy of short-term clopidogrel. Decreased response to clopidogrel was associated with limited inhibition by ARMX, an antagonist of P2Y12-receptor, suggesting the reason for clopidogrel resistance to be receptor-dependent. Conclusions: Considerable numbers of CAD patients were non-responders either to aspirin, clopidogrel or both. In the future, platelet function tests may be helpful to individually select effective and safe antiplatelet medication for these patients.
  • Hellgren, Ulla-Maija (Helsingin yliopisto, 2012)
    Indoor air in hospitals is important to both employees and patients. Complaints and problems concerning the quality of indoor air are posing an increasing challenge to occupational health and safety in hospitals. The aim of the present study was to assess the perceived indoor air quality and prevalence of indoor-air-related symptoms among hospital workers. We also determined the relationship between these factors and the condition of hospital buildings and ventilation systems. An additional aim was to find how the problem solution process functions in hospitals from the occupational health perspective. We also tested the usability of nasal lavage in patient examinations. A modified questionnaire was used to collect information on the complaints and indoor-air-related symptoms of hospital employees. Construction and ventilation professionals examined the hospitals. Semi-structured interviews concerning the processes aimed towards resolving indoor air problems were carried out among hospital personnel working in occupational health, occupational safety, and infection control. Nasal lavage was performed as part of the examinations of the employees working in a moisture-damaged hospital ward and a control group before and after the repair. Hospital employees experienced poor indoor air quality and symptoms related to indoor air more often than office workers. The workers in moisture-damaged departments had complaints and symptoms more often than the workers in departments that were in good condition. In hospitals where, for the most part, the ventilation systems were in need of repair, the workers experienced more inconvenience and symptoms than those in hospitals in which the ventilation systems were mostly in good condition. Workers in moisture-damaged departments showed signs of immune-suppression in their nasal lavage samples, and their inflammatory cell counts and cytokine levels were lower than those of the controls. Occupational health and safety personnel considered the indoor air problems difficult to tackle. The roles and responsibilities of occupational health professionals, the technical department, and the employer in solving the problems were not clear. The flow of information between the different parties clearly needed improvement. An indoor air group had been appointed in under half of the hospitals in which the interviews were carried out. These groups were considered good, especially in regard to the flow of information. In conclusion, an indoor air group should be established in every hospital. Indoor air quality should be monitored by conducting regular questionnaire surveys and walk-throughs of the buildings, and by evaluating ventilation systems. Nasal lavage needs further development before it can be applied in the occupational health tool kit for examining indoor-air-related symptoms.
  • Lehto, Juho (Helsingin yliopisto, 2007)
    Infection is a major cause of mortality and morbidity after thoracic organ transplantation. The aim of the present study was to evaluate the infectious complications after lung and heart transplantation, with a special emphasis on the usefulness of bronchoscopy and the demonstration of cytomegalovirus (CMV), human herpes virus (HHV)-6, and HHV-7. We reviewed all the consecutive bronchoscopies performed on heart transplant recipients (HTRs) from May 1988 to December 2001 (n = 44) and lung transplant recipients (LTRs) from February 1994 to November 2002 (n = 472). To compare different assays in the detection of CMV, a total of 21 thoracic organ transplant recipients were prospectively monitored by CMV pp65-antigenemia, DNAemia (PCR), and mRNAemia (NASBA) tests. The antigenemia test was the reference assay for therapeutic intervention. In addition to CMV antigenemia, 22 LTRs were monitored for HHV-6 and HHV-7 antigenemia. The diagnostic yield of the clinically indicated bronchoscopies was 41 % in the HTRs and 61 % in the LTRs. The utility of the bronchoscopy was highest from one to six months after transplantation. In contrast, the findings from the surveillance bronchoscopies performed on LTRs led to a change in the previous treatment in only 6 % of the cases. Pneumocystis carinii and CMV were the most commonly detected pathogens. Furthermore, 15 (65 %) of the P. carinii infections in the LTRs were detected during chemoprophylaxis. None of the complications of the bronchoscopies were fatal. Antigenemia, DNAemia, and mRNAemia were present in 98 %, 72 %, and 43 % of the CMV infections, respectively. The optimal DNAemia cut-off levels (sensitivity/specificity) were 400 (75.9/92.7 %), 850 (91.3/91.3 %), and 1250 (100/91.5 %) copies/ml for the antigenemia of 2, 5, and 10 pp65-positive leukocytes/50 000 leukocytes, respectively. The sensitivities of the NASBA were 25.9, 43.5, and 56.3 % in detecting the same cut-off levels. CMV DNAemia was detected in 93 % and mRNAemia in 61 % of the CMV antigenemias requiring antiviral therapy. HHV-6, HHV-7, and CMV antigenemia was detected in 20 (91 %), 11 (50 %), and 12 (55 %) of the 22 LTRs (median 16, 31, and 165 days), respectively. HHV-6 appeared in 15 (79 %), HHV-7 in seven (37 %), and CMV in one (7 %) of these patients during ganciclovir or valganciclovir prophylaxis. One case of pneumonitis and another of encephalitis were associated with HHV-6. In conclusion, bronchoscopy is a safe and useful diagnostic tool in LTRs and HTRs with a suspected respiratory infection, but the role of surveillance bronchoscopy in LTRs remains controversial. The PCR assay acts comparably with the antigenemia test in guiding the pre-emptive therapy against CMV when threshold levels of over 5 pp65-antigen positive leukocytes are used. In contrast, the low sensitivity of NASBA limits its usefulness. HHV-6 and HHV-7 activation is common after lung transplantation despite ganciclovir or valganciclovir prophylaxis, but clinical manifestations are infrequently linked to them.
  • Tulamo, Riikka (Helsingin yliopisto, 2010)
    Intracranial artery aneurysms (IAs) are estimated to be present in 2.3% of the population. A rupture of an IA causes subarachnoid hemorrhage, with up to 50% mortality. The annual low rupture risk of an IA indicates that most IAs never rupture. The current treatment options are invasive and somewhat risky. Thus rupture-prone IAs should be identified and this requires a better understanding of the IA wall pathobiology. Inflammatory cell infiltrations have been found to precede IA rupture, indicating the role of inflammation in IA wall degeneration and rupture. The complement system is a key mediator of inflammation and house-hold processing of injured tissue. This study aimed at identifying the role of complement activation in IA wall degeneration and the complement activators involved and determining how the complement system is regulated in the IA wall. In immunostainings, the end-product of complement activation, the terminal complement complex (TCC), was located mainly in the outer part of the IA wall, in areas that had also sustained loss of cells. In electron microscopy, the area of maximum TCC accumulation contained cellular debris and evidence of both apoptotic and necrotic cell death. Complement activation correlated with IA wall degeneration and rupture, de-endothelialization, and T-cell and CD163-positive macrophage infiltration. The complement system was found to become activated in all IAs by the classical pathway, with recruitment of alternative pathway amplification. Of the potential activators immunoglobulins G and M and oxidatively modified lipids were found in large areas. Lipid accumulation was observed to clearly colocalize with TCC and C-reactive protein. In the luminal parts of the IA wall, complement activation was limited by cellular expression of protectin (CD59) and extracellular matrix-bound inhibitors, C4b binding protein and factor H whereas the outer part of the wall lacked cells expressing protectin as well as matrix-bound factor H. In single nucleotide polymorphism-analysis, age-related macular degeneration-associated factor H Y402H polymorphism did not associate with the presence of IAs or their rupture The data suggest that complement activation and TCC formation are involved in IA wall degeneration and rupture. Complement seems to become activated by more than one specific activator. The association of complement with de-endothelialization and expression of several complement activators indicate a possible role of endothelial dysfunction and/or impaired clearance mechanisms. Impaired complement regulation seems to be associated with increased complement activation in IA walls. These results stress the role of chronic inflammation in IA wall pathobiology and the regulatory role of complement within this process. Imaging inflammation would possibly enhance the diagnostics of rupture-prone IAs, and targeting IA treatment to prevent chronic inflammation might improve IA treatment in the future.
  • Lindy, Otso (Helsingin yliopisto, 2008)
    The principal aim of this study was to examine diseases characterized by inflammatory injury, especially human arthritides and periodontitis, with specific interest to final effector enzymes of tissue destruction and address the possible future tools to prevent permanent tissue loss. We used biochemical and immunological methods applied to synovial tissue samples, samples of synovial fluid, and samples of peripheral blood. In Study IV, we used established clinical inflammatory injury indicator probing pocket depth and used it to derive a new clinical measure of systemic burden, periodontal inflammatory burden index. In study I, we showed a difference in the effector enzymes of peripheral blood leukocytes and leukocytes from inflamed synovial fluid of rheumatoid arthritis and reactive arthritis patients. The effector enzyme activities were higher in synovial fluid than in peripheral blood. In study II, we showed the presence of collagenase-3 in rheumatoid synovial tissue samples, relative resistance of the enzyme to inhibition in vitro and developed an electrophoretic method for detection of collagenase-3 in presence of collagenase-1. In study III, we carried out an open label study of doxycycline treatment of 12 RA patients. During the treatment period, we observed an improvement in several of the biochemical and psychosocial variables used to assess the status of the patients. In study IV, we showed a clearly lower level of periodontal inflammatory injury in chronic periodontitis patients referred for periodontal treatment. In this cross-sectional pilot study, we showed lower levels of inflammatory injury in periodontitis patients using statin than in those not receiving statin treatment. The difference was of same magnitude in patients using simvastatin or atorvastatin. The weighted index of inflammatory burden, PIBI, which emphasizes the burden imposed by the deepest pathological pockets on the system showed values consistent with a wider scale to ease future studies on the inflammatory burden associated with periodontitis.
  • Tuomainen, Anita (Helsingin yliopisto, 2009)
    Cardiovascular diseases, which presently are considered inflammatory diseases, affect millions of people worldwide. Chronic infections may contribute to the systemic inflammation suggested to increase the risk for cardiovascular diseases. Such chronic infections are periodontitis and Chlamydia pneumoniae infection. They are highly prevalent as approximately 10% of adult population and 30% of people over 50 years old are affected by severe periodontitis and 70-80% of elderly people are seropositive for C. pneumoniae. Our general aim was to investigate the role of infection and inflammation in atherosclerosis both in animal and human studies. We aimed to determine how the two pathogens alter the atherosclerosis-associated parameters, and how they affect the liver inflammation and lipid composition. Furthermore, we evaluated the association between matrix metalloproteinase-8 (MMP-8), a proteinase playing a major role in inflammation, and the future cardiovascular diseases (CVD) events in a population-based cohort. For the animal experiments, we used atherosclerosis-susceptible apolipoprotein E deficient (apoE-/-) mice. They were kept in germ free conditions and fed with a normal chow diet. The bacteria were administered either intravenously (A. actinomycetemcomitans) or intranasally (C. pneumoniae). Several factors were determined from serum as well as from aortic and hepatic tissues. We also determined how cholesterol efflux, a major event in the removal of excess cholesterol from the tissues, and endothelial function were affected by these pathogens. In the human study, serum MMP-8 and its tissue inhibitor (TIMP-1) concentrations were measured and their associations during the follow-up time of 10 years with CVD events were determined. An infection with A. actinomycetemcomitans increased concentrations of inflammatory mediators, MMP production, and cholesterol deposit in macrophages, decreased lipoprotein particle size, and induced liver inflammation. C. pneumoniae infection also elicited an inflammatory response and endothelial dysfunction, as well as induced liver inflammation, microvesicular appearance and altered fatty acid profile. In the population-based cohort, men with increased serum MMP-8 concentration together with subclinical atherosclerosis (carotid artery intima media thickness > 1mm) had a three-fold increased risk for CVD death during the follow-up. The results show that infections with A. actinomycetemcomitans and C. pneumoniae induce proatherogenic changes, as well as affect the liver. These data therefore support the concept that common infections have systemic effects and could be considered as cardiovascular risk factors. Furthermore, our data indicate that, as an independent predictor of fatal CVD event, serum MMP-8 could have a clinical significance in diagnosing cardiovascular diseases.
  • Lindström, Outi (Helsingin yliopisto, 2010)
    Acute pancreatitis (AP), a common cause of acute abdominal pain, is usually a mild, self-limited disease. However, some 20-30% of patients develop a severe disease manifested by pancreatic necrosis, abscesses or pseudocysts, and/or extrapancreatic complications, such as vital organ failure (OF). Patients with AP develop systemic inflammation, which is considered to play a role in the pathogenesis of multiple organ failure (MOF). OF mimics the condition seen in patients with sepsis, which is characterized by an overwhelming production of inflammatory mediators, activation of the complement system and systemic activation of coagulation, as well as the development of disseminated intravascular coagulation (DIC) syndrome. Vital OF is the major cause of mortality in AP, along with infectious complications. About half of the deaths occur within the first week of hospitalization and thus, early identification of patients likely to develop OF is important. The aim of the present study was to investigate inflammatory and coagulation disturbances in AP and to find inflammatory and coagulation markers for predicting severe AP, and development of OF and fatal outcome. This clinical study consists of four parts. All of patients studied had AP when admitted to Helsinki University Central Hospital. In the first study, 31 patients with severe AP were investigated. Their plasma levels of protein C (PC) and activated protein C (APC), and monocyte HLA-DR expression were studied during the treatment period in the intensive care unit; 13 of these patients developed OF. In the second study, the serum levels of complement regulator protein CD59 were studied in 39 patients during the first week of hospitalization; 12 of them developed OF. In the third study, 165 patients were investigated; their plasma levels of soluble form of the receptor for advanced glycation end products (sRAGE) and high mobility group box 1 (HMGB1) protein were studied during the first 12 days of hos-pitalization; 38 developed OF. In the fourth study, 33 patients were studied on admission to hospital for plasma levels of prothrombin fragment F1+2 and tissue factor pathway inhibitor (TFPI), and thrombin formation capacity by calibrated automated thrombogram (CAT); 9 of them developed OF. Our results showed significant PC deficiency and decreased APC generation in patients with severe AP. The PC pathway defects seemed to be associated with the development of OF. In patients who developed OF, the levels of serum CD59 and plasma sRAGE, but not of HMGB1, were significantly higher than in patients who recovered without OF. The high CD59 levels on admission to the hospital seemed to be predictive for severe AP and OF. The median of the highest sRAGE levels was significantly higher in non-survivors than in survivors. No significant difference between the patient groups was found in the F1+2 levels. The thrombograms of all patients were disturbed in their shape, and in 11 patients the exogenous tissue factor did not trigger thrombin generation at all ( flat curve ). All of the patients that died displayed a flat curve. Free TFPI levels and free/total TFPI ratios were significantly higher in patients with a flat curve than in the others, and these levels were also significantly higher in non-survivors than in survivors. The flat curve in combination with free TFPI seemed to be predictive for a fatal outcome in AP.
  • Jussila, Airi (Helsingin yliopisto, 2014)
    Inflammatory bowel diseases (IBDs), Crohn´s disease (CD) and ulcerative colitis (UC) are characterized by chronic mucosal inflammation and subsequent lesions in the colon or even throughout the gastrointestinal tract with involvement of other organs. They are chronic inflammatory conditions with long-term morbidity and often requiring expensive healthcare. The aetiology of IBD has remained obscure and is thought to be multifactorial. Over the past few years IBD has become a global disease. Western European and North American countries have been traditionally high incidence and prevalence areas. During the last decade, increasing incidence rates has also been observed in Eastern Europe and Asia. It has been suggested that the incidence of IBD has stabilized or slightly increased in Western countries with even decreasing incidence rates for UC in some Western countries. However, new epidemiological data suggest that the incidence and prevalence of the diseases are still increasing in most countries, including Western countries. A North-South gradient has been identifiedfor IBD. In Europe, higher incidence rates have been found in Northern countries. In several countries including the USA, UK and France, North-South gradients have also been reported. Patients with long-lasting IBD, both UC and CD colitis, have been at increased risk of developing colorectal cancer (CRC) and CD patients are at increased risk of small intestine cancer. In most recent studies the risk of CRC has decreased and in some studies no increased risk of CRC has been seen in IBD overall. Male sex, young age at diagnosis, extensive colitis and primary sclerosing cholangitis (PSC) have been shown to increase the risk. Chronic colonic inflammation in UC or CD results in an increased risk of cell proliferation and colon carcinogenesis. Studies have supported the severity of microscopic inflammation as an independent risk factor for dysplasia and CRC in patients with long-standing UC. Patients with CD are at elevated risk of developing extra-intestinal cancers compared to UC patients, whose risk seems to be similar to that of general population. CD patients are at increased risk of developing cancer of the upper gastrointestinal tract, lung, urinary bladder and skin. Patients with UC have a significantly increased risk of liver-biliary cancer, but a decreased risk of lung cancer. Recent studies have shown an increased risk of non‐melanoma skin cancers (NMSCs) in IBD patients, especially in those taking thiopurines. An increased risk of lymphoma has also been observed among IBD patients taking thiopurines. IBD can cause increased mortality. The research on overall and cause-specific mortality in IBD is to some extent contradictory. Earlier studies have documented a slightly increased overall mortality for UC patients compared with general population but most studies have reported no increased mortality risk. In contrast to UC, overall mortality for patients with CD has been increased according to most studies. Among patients with UC mortality from CRCs, gastrointestinal, respiratory and nonalcoholic liver diseases has been increased. The increased mortality among CD patients has been attributed an excess of mortality in gastrointestinal, respiratory, genitourinary, infectious and nonalcoholic liver disease. This thesis aims to evaluate overall burden of IBD in Finland by estimating the nationwide incidence of IBD during the period 2000 2007 and the nationwide prevalence of IBD and changes in the prevalence from 1993 to 2008 by analysing the unique, comprehensive Finnish reimbursement database. Our aim was also to test the North-South gradient hypothesis. We moreover had an opportunity to study vitamin D levels in Finland in the Health 2000 Survey. Our aim was also to assess the long-term risks of malignant diseases and the overall and cause-specific mortality among patients with IBD in a nationwide study in Finland. Finally, our aim was to assess whether the degree of microscopic inflammation is a risk factor for developing dysplasia or CRC in IBD, and to specify the risk for developing dysplasia in patients with no inflammation to better target surveillance in IBD.
  • Denisova, Oxana (Helsingin yliopisto, 2014)
    Influenza viruses cause pandemics and annual epidemics which have serious consequences for public health and global economy. The severity of infections with influenza viruses can vary from asymptomatic to life-threatening viral pneumonias. Currently, four licensed anti-influenza drugs are available for the prevention and treatment of influenza virus infections. However, resistance to the licensed antivirals develops rapidly. Therefore, there is a need for next-generation antiviral agents to combat influenza virus infections. Recent advances in understanding influenza virus-host interactions have revealed a number of host targets for potential antiviral interventions. In particular, basic cellular functions, metabolic and biosynthesis pathways, as well as the signaling cascades could be modulated by small-molecule inhibitors to block virus infection. Moreover, temporal inhibition of these host functions will be less likely to induce viral drug resistance. In addition, many of the inhibitors of cellular functions are already approved or in clinical development for other diseases. Drug repurposing will facilitate their introduction for treatment of viral infections, since the pharmacokinetics and toxicity profile of these drugs are already known. In this work, a library of small-molecule inhibitors targeting host factors and potentially interfering with influenza virus infection was built and screened. Inhibitors of vacuolar proton-ATPase (v-ATPase), Akt kinase, ribonucleotide reductase and the anti-apoptotic B-cell lymphoma-2 family proteins showed antiviral activity in vitro. Saliphenylhalamide, an inhibitor of v-ATPase, was the most potent antiviral agent and it was effective against a broad range of influenza viruses and some other RNA viruses in vitro, and against a mouse adapted influenza strain in vivo. In order to overcome the low water solubility and high toxicity of saliphenylhalamide, bioavailability was optimized using a porous silicon particle-based delivery system for the putative clinical trials. The results presented in this study expand the understanding of influenza virus-host interactions, and provide a novel perspective for ways to adopt a rational approach in the discovery of new antiviral agents.