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  • Reponen, Elina (Helsingin yliopisto, 2016)
    Background: Preoperative risk assessment and reliable outcome reporting are vital for improving quality of care and patient safety. Studies on neurosurgical patients are surprisingly scarce, and no prospective reports on unselected elective craniotomy patients exist. The objectives of this study were to review the literature on the use of preoperative risk-assessment scores in elective cranial neurosurgery and to study preoperative risk prediction, short-term outcome reporting, and patient satisfaction in the first unselected, prospective cohort of adult elective craniotomy patients. Patients and Methods: We performed a systematic review of 25 studies on five preoperative scores [The American Society of Anesthesiologists physical status classification (ASA) score, the Karnofsky Performance Score (KPS), the modified Rankin Scale (mRS), the Sex, Karnofsky, ASA, Location, and Edema (SKALE) score, and the Charlson comorbidity score] in predicting outcome in elective cranial neurosurgery. We enrolled a prospective, unselected cohort of 418 adult elective craniotomy patients in the Department of Neurosurgery, Helsinki University Hospital. Evaluation of routinely collected preoperative data, original ASA score, Helsinki ASA score, and their combinations revealed their ability to predict in-hospital new central nervous system (CNS) deficits as well as systemic and infectious complications after elective craniotomy. We evaluated the reliability and accuracy of patient-reported outcomes, postoperative mRS scores, and mRS-score differences in reflecting short-term outcome. Overall patient satisfaction rate was determined, as were associations between high or low patient satisfaction and short-term postoperative outcome. Results: Evidence as to the applicability of preoperative risk-assessment scores in elective cranial neurosurgery is scarce, with KPS receiving the most support in the literature. None of the scores predicted all postoperative outcomes; the most applicable risk score varied with the outcome measure selected. The in-hospital mortality rate was 1.0% and the 30-day rate was 2.4%. In-hospital systemic and infectious complications occurred in 6.7% of patients, and new CNS deficits in 11.2%. Advanced age, preoperatively elevated C-reactive protein (CRP) level, and high Helsinki ASA class were independent predictors of systemic and infectious complications. A combination of these variables identified one-fourth of the patients with systemic and infectious complications (p=0.005, OR 4.8, CI 1.5-15.9, AUC 0.766) and was associated with prolonged intensive care unit (ICU) stay (p=0.018) and hospital stay (p=0.004). The rate of overall complications was 46.4%, and the rate of major complications was 18.2%. Perioperative changes in mRS scores were inconsistent: among patients with no complications, the mRS score increased for 17.1% at hospital discharge and for 23.8% at 30 days. Moreover, 28.0% of patients with major complications showed no increase in mRS scores at hospital discharge. Associations between patient-reported postoperative subjective deterioration in functional status and both major and overall morbidity were significant. Furthermore, a simple unweighted composite score of PROs was more sensitive and specific than was 30-day dependent functional status (mRS score ≥3) in detecting both major and overall morbidity. In our cohort, 93.8% rated their overall satisfaction as good or excellent. Even 9 of 10 patients with postoperative major morbidity rated their satisfaction as high. Low patient satisfaction was associated neither with major (p=0.054) nor with overall (p=0.215) morbidity. Conclusions: Strong evidence supporting the use of any preoperative risk score in elective cranial neurosurgery is lacking. The Helsinki ASA score seems more suitable than the original ASA score for elective craniotomy patients, especially in combination with other preoperative risk predictors, but only for systemic and infectious complications. The rate of major complications in our cohort was moderately low considering the average age, comorbidities and operated lesions of the patients in our unselected study cohort. The postoperative mRS score and mRS-score differences were inconsistent with recorded complications, whereas PROs seem promising tools for outcomes reporting. Overall patient satisfaction was high, even in patients with complicated outcomes, and thus patient satisfaction is a poor proxy for treatment outcome and quality of care in elective cranial neurosurgery.
  • Quintero, Ileana B. (Helsingin yliopisto, 2015)
    Prostatic acid phosphatase (PAP) has been linked to prostate cancer since the mid-1930s. The main research approach of PAP over that time has been based on its role in the human prostate. The regulatory mechanisms of expression of the PAP gene have also been studied, giving us information about the regulatory elements in the gene and the transcription factors that affect the gene expression in the prostatic tissue. However, little was known until recently about this protein s role and physiological function in other tissues. Our group generated and used a PAP-deficient mouse and was able to show that PAP is expressed in dorsal root ganglia (DRG) and spinal cord in mice. This is the same protein as thiamine monophosphatase (TMPase) whose enzymatic activity has been used for five decades to mark primary sensory neurons. In these tissues, PAP acts as an ecto-5'-nucleotidase and is able to dephosphorylate AMP to adenosine, and therefore produce an anti-nociceptive effect due to the binding of adenosine to the A1-adenosine receptor. We analyzed the ACPP gene, which enabled us to describe a new transmembrane isoform for PAP (TMPAP). This novel PAP isoform is produced by alternative splicing of the 11th exon of the ACPP gene. The alternative splicing is present in species such as the human, mouse and rat. The newly discovered isoform is widely expressed in human and mouse tissues and contains a tyrosine sequence (YxxΦ) in its carboxyl-terminus, which directs the protein to endocytosis. We have also corroborated its functionality by co-localization studies with different organelle markers in the endosomal/lysosomal pathway (I). The generation of a PAP-deficient mouse also enabled us to study the function/s of PAP in vivo. The lack of PAP in this mouse model led to the gradual changes in the mouse prostate that finally culminated with the development of prostate adenocarcinoma at the age of 12 months. Microarray analyses of different tissues that compared the PAP deficient mouse with the wild type (WT) mouse revealed changes in genes related to the vesicular trafficking, which support our previous results and led us to the conclusion that TMPAP could be involved in the regulation of the vesicular trafficking. We also detected the interaction between TMPAP and snapin, a SNARE (Soluble NSF Attachment Protein Receptor) associated protein, by yeast two-hybrid screening, co-localization and FRET (Förster resonance energy transfer) analysis. We concluded that, the disruption of this interaction in the PAP-deficient mouse leads to a disturbance in the vesicular transport of the cell and to the development of prostate adenocarcinoma in the PAP-deficient mouse prostate (II). Furthermore, we showed that the PAP-deficient mice present multiple behavioral and neurochemical alterations including increased size of brain lateral ventricles, hyperdopaminergic deregulation, and altered GABAergic transmission, symptoms that indicate that PAP also disturbes the normal function of the central nervous system (III). Snapin protein in the brain has been described as a protein important for the vesicular transport and for the fusion of vesicles with the plasma membrane, and we observed that the lack of PAP in GABAergic neurons leads to a change in the localization of snapin in the PAP-deficient mouse (III), which could indicate that as in the prostate a dysregulated vesicular trafficking could be the reason for the detected phenotype. The discovery of the new TMPAP and its localization in the endosomal/lysosomal pathway enabled an understanding of the phenotypic changes that occur in the PAP-deficient mouse. We hypothesized that TMPAP regulates vesicular trafficking by interacting with snapin, and its deficiency leads to a dysregulation of the endo-/exocytosis cycle, which produces the observed alterations in the mouse organs and tissues. The results obtained throughout this research project have opened up new lines of research related to PAP physiological function, and a deeper understanding of the expression, regulation and function of this protein could lead to new clinical applications.
  • Puranen, Taija (Helsingin yliopisto, 2015)
    Nutritional problems such as poor appetite and unintentional weight loss are common among individuals with Alzheimer’s disease (AD), and their older spousal caregivers with comorbidities may also be at risk of malnutrition. The objective was to study the nutrition of people with AD and their spouses, and to compare nutrient intake to recommended levels, and to investigate the association between the caregiver’s gender and the couples’ nutrition. A randomized, controlled trial was conducted to examine the effectiveness of nutritional guidance on the AD victim’s weight, nutritional status (MNA), energy and nutrient intake (three-day food diaries), quality of life (HRQoL with 15D) and falls. A total of 99 couples were randomized into this trial. The intervention group (IG) received tailored nutritional guidance 4-8 times at their homes over one year, and the control group (CG) received booklet on healthy nutrition. The primary outcome measure was the AD sufferer’s weight change. The mean age of AD was 77.4 years (SD 5.6), and spouses 75.2 years (SD 7.0). At baseline, 44% of the AD, and 16% of the spouses were at risk of malnutrition, whereas 56% and 84% had a good nutritional status. At baseline, the mean energy intake among those with AD was 1897 kcal (SD 416) among the men and 1313 kcal (SD 340) among the women, and the respective figures for spousal caregivers were 1605 kcal (SD 458) and 1536 kcal (SD 402). Among AD, 47% of the men and 71% of the women had a protein intake below 1g /bodyweight/kg, the respective figures for the spouses being 71 and 49%. In addition, almost half of the participants had a vitamin C intake of less than the recommended. The male gender of the caregiver was associated with poor energy and nutrient intake in the couple. Tailored nutritional guidance had no effect on the weight of those with AD, but improved their nutrient intake and HRQoL. The mean change in protein intake was 0.05 g per body/kg in kg (95% CI -0.06 to 0.15) in the IG, and -0.06 g per body/kg in the CG (95% CI -0.12 to 0.02), p = 0.031. The respective changes in mean calcium intake were 85 mg (95% CI -24 to 194) and -17 mg (95% CI -98 to 65), p = 0.025. HRQoL improved by 0.006 (95% CI -0.016 to 0.028) in the IG, and declined by -0.036 (95% CI -0.059 to 0.013) in the CG, p = 0.007. In addition, those in the IG with AD had a significantly lower number of falls than those in the CG during the one year: 0.55 (95% 0.34 to 0.83) and 1.39 (95% CI 1.04 to 1.82) falls per person, p < 0.001, respectively. The community-dwelling ID sufferers and their spousal caregivers were very heterogeneous in terms of nutrition. Male caregivers may need tailored guidance on food-related activities. Tailored nutritional guidance improves both nutrition and the quality of life among those with AD, and may also prevent falls, and should therefore be part of their everyday care.
  • Heikinheimo-Connell, Terttu (Helsingin yliopisto, 2015)
    Background: Stroke is the second most common cause of death. It is also the leading cause of disability worldwide. Low-income countries, where infectious diseases play a major role, carry the biggest burden of growing numbers of stroke. Infections can trigger an acute stroke. Malawi is situated in Sub-Saharan Africa, where prevalence of chronic diseases like high blood pressure, diabetes mellitus, and stroke are increasing. The HIV-prevalence among young adults is 12%. HIV may cause milder neurocognitive impairments, which are called HIV-associated neurocognitive disorders (HAND). Methods: The Helsinki Young Stroke Registry (HYSR) includes over 1000 patients aged 15-49 years with acute ischemic stroke. We investigated how high leukocyte count and infections affect recovery after stroke. In Malawi, we defined the stroke characteristics, impact of HIV, and one-year outcome. A selected subset of patients were interviewed about their quality of life (QOL). A group of Finnish men were investigated to determine whether HIV has caused neurological or neurocognitive impairment when with best available treatment for even 30 years. Results: In Helsinki (781 patients) high leukocyte count weakened 3-month outcome, however, not the long-term outcome (8.1±4.2 years). In the other study (681patients) 10% had preceding infection (PI), most commonly upper respiratory tract infection, and 15% had post stroke infection (PSI), most commonly pneumonia. All the infections worsened 3-month outcome. PSI was associated with long-term (7.8±4.0 years) higher risk of all-cause death. In Malawi (147 patients) HIV-infected patients (34%) suffered more often from ischemic stroke than HIV-negative patients. They were younger and had less often conventional risk factors for stroke. More than half of all patients had a poor outcome at 1-year, and the mortality rate was 45%. This was related to stroke severity and female gender but not to presence of HIV. We interviewed 25 patients. Good functional outcome was positively associated with better QOL on the domains of self-care and ability for communication. Females scored worse on the domains of fatigue and cognition. Older age was associated with worse QOL on the domain of self care. HIV did not affect the QOL. We evaluated 17 Finnish HIV-patients. A third had signs of polyneuropathy, half suffered from fatigue, and mild depression was common. Magnet resonance image (MRI) showed signs of lacunar ischemic stroke in three patients. Conclusions: The high leukocyte count in HYSR patients was associated with vascular disease and stroke severity. The high leukocyte count, PI and PSI were associated with poor short-term outcomes. PSIs were also associated with higher long-term mortality. In Malawi, severe stroke and gender were associated with unfavorable outcome. HIV-infection is common especially among young stroke patients, but not related to unfavorable outcome. QOL was associated with age, gender, and functional recovery. Despite HIV, the surviving Finnish patients had no describing features of HAND. Polyneuropathy, fatigue and mild depression were common. The silent strokes in MRI support the hypothesis of HIV increasing the risk of strokes.
  • Kandolin, Riina (Helsingin yliopisto, 2015)
    Cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) are underdiagnosed inflammatory myocardial diseases. Sarcoidosis is a systemic disease characterized by granuloma formation and subsequent tissue scarring in various organs, most commonly in the lungs. In majority of cases, lung sarcoidosis is a self-limiting disease whereas cardiac involvement carries a poorer prognosis due to heart failure and malignant arrhythmias. GCM is a rare, frequently fatal myocardial disease designated by widespread myocardial inflammation and necrosis. Prior data concerning epidemiology, outcome with contemporary treatment and ICDs, and the effect of novel diagnostic methods is scarce and I set out to study these questions. All cases with histologically confirmed CS and GCM in Finland between 1988 and 2014 were identified and analyzed. A marked increase in the detection rate of CS over the last 26 years was found. In the era of modern diagnostic imaging and increased awareness, the annual detection rate of CS is over 50 times higher than before. CS most commonly manifests with atrioventricular block (AV-block). What is more, CS and GCM together explain 25% of initially idiopathic 2nd to 3rd degree AV-blocks in adults aged 18-55 years. Other principal manifestations of CS are heart failure and ventricular arrhythmias. Two thirds of patients with CS present without prior diagnosis of sarcoidosis, an entity called clinically isolated CS. The mean age of CS patients was 51 years and two thirds were female. The diagnosis was based on endomyocardial biopsy (EMB) in 50% of cases and on extracardiac biopsy combined with cardiac imaging findings (cardiac magnetic resonance (CMR) or positron emission tomography (PET)) in 50% cases. Single EMB session had a sensitivity of approximately 30% in detecting CS, but repeated biopsies or taking histologic samples from mediastinal lymph nodes markedly improved the diagnostic yield. In majority of cases, CS is a slowly progressive cardiomyopathy. With up-to-date diagnostic methods and treatment, 99% of patients were alive without cardiac death or transplantation at 1 year and 91% after 10 years from symptom onset. The most common presentations in GCM patients were heart failure and AV-block. Moreover, ventricular arrhythmias were common with two third of patients experiencing sustained ventricular tachycardia or ventricular fibrillation during the disease course. With current diagnostic methods and therapy with a combination of immunosuppressants, the transplant free survival was 69% at 1 year and 52% at 5 years. In conclusion, the detection rate of CS and GCM in Finland is increasing and the prognosis with contemporary diagnostic and therapeutic methods seems better than previously reported.
  • Kivistö, Kaisa (Helsingin yliopisto, 2015)
    Illicit use of prescription opioids has increased markedly in recent years, especially in Europe and North America. In Finland, the number of opioid problem users constantly increased through the 2000s, levelling off in 2012. Buprenorphine is a semisynthetic opioid that was originally administered as an analgesic, but later also used in opioid detoxification and maintenance treatment. However, buprenorphine abuse has been reported in many countries. In Finland, buprenorphine is the most common injection drug. Buprenorphine use in late pregnancy leads to neonatal abstinence syndrome (NAS) in roughly 60% of newborns. Data on buprenorphine-exposed children´s health after the neonatal period is scarce. Our aim was to identify the health problems of these children from infancy to three years of age. The study population comprised altogether 108 children with a positive drug screen for buprenorphine as a newborn. Children were born in 2000s in Helsinki University Central Hospital (HUCH). One main finding was that pediatricians observed multiple types of child abuse and neglect in the study population in HUCH. Pediatricians made altogether 70 child welfare reports. Repeated failure to come to an appointment, which was considered medical neglect, constituted 64% of the child welfare reports. In four children, physical abuse was suspected. Another main finding was that buprenorphine-exposed children had significantly more early childhood caries than control children. The study raised concern for dental neglect in buprenorphine-exposed children. We also discovered that 10% of buprenorphine-exposed children had been diagnosed with strabismus and 5% had a major congenital anomaly. Of 102 children, four had an umbilical or inguinal hernia and three had infantile pyloric stenosis. The psychological study revealed poorer cognitive abilities in buprenorphine-exposed children at three years old than in controls as well as reduced performance of mother-child dyads in terms of emotional availability and perceived maternal self-efficacy. In the MEG study, somatosensory and auditory evoked potentials did not show significant differences between the buprenorphine-exposed group and the control group. Prenatally buprenorphine-exposed children exhibit more early childhood caries and dental neglect than control children. In addition to dental neglect, the children are exposed to multiple types of child maltreatment as well as to unfavorable emotional features in the caregiver-child relationship. Based on health and maltreatment issues revealed here, a pediatric follow-up with a multi-professional team, including a dentist, is essential.
  • Koho, Petteri (Helsingin yliopisto, 2015)
    Psychological factors are implicated in the transition from acute to chronic back pain as well as in predicting return to work in low back pain patients. Research shows that pain-related fear can be more disabling than pain itself. Earlier studies have demonstrated that fear of movement and fear of (re)injury are better predictors of functional limitations than biomedical parameters. During clinical assessment chronic pain patients frequently demonstrate a variety of pain-associated behaviours. These behaviours may also influence development of chronic pain and disability. The purpose of the research project was; to develop a functional assessment tool for the assessment of pain behaviour and to investigate the relationship between pain behaviour, fear of movement, physical function, and disability, and to study the association between fear of movement and leisure time physical activity (LTPA) among chronic pain patients, and to estimate the measurement properties of the Finnish version of the Tampa Scale of kinesiophobia (TSK-FIN) among chronic pain patients, and to investigate fear of movement among the general population. The functional assessment tool for the assessment of pain behaviour showed good reliability. There was a strong correlation between pain behaviour and subjective pain report and disability and moderate correlation to pain behaviour. The inverse associations between total pain behaviour and physical function tests were strong. The internal consistencies were good and test-retest reliability of the TSK-FIN was excellent for both paper and computer versions. The mean difference between the computer and the paper version was 1.9. However, in terms of individual variability, 62% varied by less than 3 points and 44% by less than 2 points. The level of kinesiophobia was associated with disability and depressive symptoms. Kinesiophobia and leisure time physical activity were inversely associated. For the purpose of the studying the effect of pain management program, the patients were classified into three groups based on distribution of the TSK-FIN. At baseline, the mean LTPA index of the high kinesiophobia group was lower than in the low and medium kinesiophobia groups. At the 6-month follow-up, patients with high kinesiophobia had increased their physical activity to the same level as the other groups. This change was maintained up to the 12-month follow-up. Among general population, men over 55 and women over 65 had higher scores than younger ones. The presence of cardiovascular disease, musculoskeletal disease or mental disorder was significantly associated with a higher TSK-FIN score compared to the absence of the aforementioned disorders. Among general population, 14.2% received the generally used cut-off point 40 points or more for increased kinesiophobia. Conclusion: The results of this research project suggest that both the assessment of pain behaviour and the TSK-FIN demonstrated acceptable reliability. Among patients with musculoskeletal pain, the fear of movement and leisure time physical activity are inversely related. A pain management program seems to have favourable effect on the fear of movement and physical activity. Among general population age and TSK-FIN score are associated. Among general population, 14 % scored over cut-off point 40 points or more.
  • Saksi, Jani (Helsingin yliopisto, 2015)
    Carotid artery disease is a common cause of stroke, with approximately one in five ischemic strokes in the carotid artery distribution stemming from thromboembolisms caused by an unstable atherosclerotic carotid plaque (CP). Despite the fact that carotid atherosclerosis can lead to cerebrovascular complications, some patients afflicted by a high-grade carotid stenosis (>70%) remain asymptomatic. This divergence in clinical courses captures one of the most pressing questions in cardiovascular medicine: what are the key molecules and pathways decisive to local atheroma vulnerability and connected with disabling clinical outcomes? In the first paper, we utilized a genome-wide approach to screen for gene expression changes in stroke-associated CPs to identify genes and pathways related to atheroma vulnerability and symptom generation. This approach was successful in identifying several significant expression changes in novel genes and in genes already connected with atherosclerosis development, suggesting that the local atheroma-derived gene expression patterns are closely connected to the patient s clinical phenotype. A detailed data-driven approach, using three independent data pre-processing methods, identified fatty acid-binding protein 4 (FABP4) as the lead hit overexpressed in stroke-associated CPs, thus linking FABP4 and its transcriptional activity to atheroma vulnerability. Immunohistochemical analysis revealed the most prominent expression of FABP4 protein in the histological regions of atheroma vulnerability, coinciding with the abundance of lipid-laden macrophages and thus connecting the overexpression of FABP4 with lipid accumulation and inflammation within the CPs. In the second paper, we focused on the molecular mechanisms through which increased FABP4 expression could regulate atheroma vulnerability. As causality is difficult to infer from associative expression data we adapted a genetic approach searching for variants that could regulate the expression of FABP4. Using a naturally occurring low-expression variant (rs77878271) we were able to link genetically reduced atheroma expression of FABP4 to endoplasmic reticulum (ER) stress signaling, and the attenuation of apoptosis, with high expression contributing to increased lipid burden and inflammation. We discovered that the low-expression variant of FABP4 was associated with lower circulating total cholesterol levels, with the lowest levels in obese (body mass index, BMI ≥ 30) minor allele homozygotes. Furthermore, the variant allele carriers showed obesity-related reduction in subclinical markers of atherosclerosis, manifested as reduced carotid intima-media thickness (IMT) and lower prevalence of CPs. Most importantly, we found that the local atheroma effects of FABP4 penetrated to end point level, as the minor allele homozygotes showed 8-fold lower odds for myocardial infarction (MI) and enrichment of the variant in patients with clinically asymptomatic carotid artery disease. Obesity-related reduction of total cholesterol levels observed in the low-expression variant carriers pointed to a metabolic component mediated by genetically reduced FABP4 expression. Based on the discoveries made in FABP4-deficient mouse models, we hypothesized that genetically reduced FABP4 expression could lead to sustained enhancement of adipocentric de novo lipogenesis (DNL), which could in part explain the obesity-related phenotypes also in man. We found that the low-expression variant of FABP4 was associated with circulating markers of enhanced lipolysis and reduced circulating FABP4 protein levels. The variant allele carriers showed a propensity for higher BMI, with evidence for enhancement of DNL, improved beta-cell function, and reduced obesity-related type 2 diabetes (T2D) risk. These results imply that FABP4-regulated production of adipocyte-derived lipid signals during DNL in the low-expression variant carriers may in part lead to enhanced beta-cell function and reduced obesity-related T2D risk. In this thesis work, we identified FABP4 as a key molecule at the crossroads of metabolic and inflammatory responses, potentially involved in local atheroma vulnerability and connected with cardiometabolic outcomes. Most likely the role of FABP4 in atherosclerosis is multifaceted, converging with the passage of time within the artery atheroma, and culminating in the regulation of inflammatory responses affecting cell survival, acute plaque vulnerability and ultimately cardiovascular risk. These data implicate FABP4 as a potential pharmacological target for prevention of cardiometabolic complications connected with atherosclerosis and obesity.
  • Heikkilä, Jukka (Helsingin yliopisto, 2015)
    ABSTRACT Background. Posterior urethral valves (PUV) constitute the most common infravesical urinary obstruction in boys. PUV are often accompanied by severe consequences to the lower and upper urinary tract. They also represent a major urological cause for paediatric renal transplantations. Since no previous systemically analysed true long-term studies exist, early findings, treatment and their relations to late renal function are not clarified in many respects. Aims. The clinical characteristics and renal outcomes of PUV were assessed. Also evaluated were the risk factors for the progression to end-stage renal disease (ESRD). Patients and methods. All patients treated for PUV at Children s Hospital, University of Helsinki, from 1953 to 2003 were identified from the hospital database. Age and mode of presentation, structural abnormalities, treatment, follow-up data and outcome were registered. In addition, the Finnish Kidney Transplantation Registry and the Finnish Population Register were reviewed to identify those who had progression to dialysis or renal transplantation or had demised. Results. The diagnosis of PUV was made in 200 patients. The incidence of cryptorchidism was16-fold and the incidence of inguinal hernia 7-fold higher in PUV patients than in the normal population. Cryptorchidism and inguinal hernias was more common in patients with more severe PUV. The incidence of urinomas in PUV patients was 15% after onset of routine ultrasound. Of all 17 patients, 9 had perirenal urinoma, 6 urinary ascites and 2 urinothorax. Renal function was similar in PUV patients with and without urinoma. High voiding pressures were seen in infants around the ablation of the valves. No correlation between high voiding pressures and poor primary kidney function was observed. The voiding pressures were registered to decrease during the months following the release of the valvular obstruction. Vesicoureteral reflux (VUR) was observed in 127 PUV patients (64%). Bilateral VUR was present in 73 (37%) and unilateral VUR in 54 (27%). At presentation, refluxing patients had significantly higher serum creatinine values than patients without VUR. Reflux resolved spontaneously at a median of 1.28 years (range 0.04 to 15.16) after the release of the valvular obstruction. Of all patients, 44 (22.8%) had progression to ESRD at the evaluation, which occurred at a median age of 31 years (range 6 to 69); 30 (68%) had developed renal failure before the age of 17 years, and 14 (32%) as adults. In this study, the highest age at the onset of ESRD was 34 years. According to Kaplan-Meier analysis, the life-time risk of ESRD was 28.5% (SE 3.8%). Patients with higher creatinine values during the first postoperative year had progression to ESRD at an earlier age. Early age, poor renal function, pneumothorax and bilateral VUR at presentation and postoperative recurrent urinary tract infections (UTI) were risk factors for ESRD. Conclusions. Posterior urethral valves often lead to ESRD. Early presentation, poor primary renal function, pneumothorax perinatally as well as VUR bilaterally and recurrent postoperative UTIs carry a risk for renal function deterioration and ESRD. These risk factors should be recognized and proper management initiated, with follow-up extending through childhood to adulthood.
  • Karppinen, Atte (Helsingin yliopisto, 2015)
    Pituitary adenomas are the most common tumors of the sella turcica. Our objectives here were to describe the transitional phase from microscopic to endoscopic surgery for nonfunctional pituitary adenomas (NFPAs), and to outline the health-related quality of life (HRQoL) and its determinants after treatment of different pituitary adenomas in a recent cohort from a single pituitary center. We retrospectively collected the relevant data for a total of 320 patients who had undergone primary surgery for a newly diagnosed pituitary adenoma during 2000-2010 at Helsinki University Hospital. The first part of our study included 185 consecutive patients who had transsphenoidal surgery for NFPA. These patients were divided into two groups based on the surgical approach: microscopic and endoscopic. Surgical and endocrinological outcomes were assessed at the 3-month follow-up. The second part of our study used a cross-sectional design and comprised all pituitary adenoma types. Each patient alive was sent a questionnaire (the 15D) assessing the HRQoL a mean of 7.4 years after the primary transsphenoidal surgery. One hundred functional pituitary adenoma (FPA) and 137 NFPA patients responded. We then compared HRQoL (15D scores) between patients and a large sample of an age- and gender-standardized Finnish general population. Independent factors influencing the overall HRQoL (mean 15D score) were estimated using multivariate analysis. A good short-term surgical outcome could be achieved during the initial phase of transition from microscopic to endoscopic transsphenoidal surgery for NFPA patients. Our first endoscopic single-center consecutive case series showed a trend towards improved tumor control but the operative time was longer than with the microscopic technique.The effect of NFPA surgery on pituitary function (hypopituitarism) in both surgical groups was neutral. Current multimodal treatment protocols with optimized hormonal replacement therapies enabled normal or at least near-normal overall HRQoL to be achieved in the majority of patients with all types of pituitary adenomas. Hormonal remission rate of FPAs was 91%. However, patients with Cushing s disease and NFPA had clinically and statistically significant impairments of some single dimensions compared with the general population. Comorbidities were strong determinants of compromised overall HRQoL in patients treated for pituitary adenomas.
  • Koskela, Jukka (Helsingin yliopisto, 2015)
    Managing chronic respiratory conditions such as asthma and Chronic Obstructive Pulmonary Disease (COPD) forms a notable burden on the healthcare system while the burden on an individual is equally notable as patients might suffer from a symptomatic disease for decades. However, not all asthma and COPD patients develop a disabling disease with frequent disease exacerbations and highest cost (in Quality Adjusted Life Years lost or healthcare spending). This variation in disease trajectories enables the analytical identification of distinct phenotypes over time. Retrospective data collected from a large number of patients could be used efficiently as the electronic health records are increasingly made available to researchers around the world. The aim of this project is to develop disease models based on longitudinal data to better capture the essential characteristics of obstructive lung disease, mainly focusing on COPD. Projects I III in this thesis are based on 2398 asthma and COPD patients retrospectively followed through electronic health records from year 2000 onwards. We aimed to analyse this real-world hospital based data using Hierarchical Models to assess the variation of development between individual patients over time. Unpublished Project IV is based on Health 2000 to 2011 follow-up study consisting of 1113 subjects from random Finnish population. The aim was to estimate Single Nucleotide Polymorphism (SNP) based heritability of Forced Expiratory Volume in 1 s (FEV1) level and development and to perform a Genome-Wide Association Study (GWAS) to identify possible genetic markers associated with FEV1 development over time. Our results suggest that the major determinants of Health Related Quality of Life (HRQoL) in mild or moderate COPD are the common comorbidities associated with COPD while in severe diseases the accentuated lung function has a major role. Over time, observable individual trajectories of HRQoL are presented in Asthma and COPD. Significant decline of HRQoL in Asthma was found to associate with obesity related diseases and states while the main determinants in COPD were poor lung function and increasing age. Psychiatric conditions were found associated in both Asthma and COPD. Using an unbalanced data (varying number of measurements and length of follow-up time) of lung function measurements, we were able to observe significant individual trajectories of FEV1 based on the past development. Significant and rapid decline was seen in 30% of the COPD cohort in the study while significant improvement was extremely rare. Rapid decline was associated with numerous exacerbation related markers. Our unpublished results suggest that development of FEV1 is significantly affected by common variants in DNA as genetic effects were estimated to explain 1/3 of the phenotypic variance in random Finnish population. One locus previously associated with the level of FEV1 was found associated with the development of FEV1. Suggestive evidence for two novel loci associated with FEV1 development was also identified. The findings underline the varying trajectories of HRQoL and lung function seen in a homogenous cohort of Asthma and COPD patients. This thesis aims to provide approaches and aspects to better understand the trajectories of a chosen parameter in asthma and COPD. The variation of e.g. lung function development is abundant, and we should not consider this variation as an obstacle but as a useful source of information as there might be genetic or environmental determinants causing this variation.
  • Oksanen, Tuomas (Suomen Ensihoidon Tiedotus Oy, 2015)
    Aims of the study Intensive care is usually necessary for the good survival of postresuscitation patients. The use of some intensive care methods can make the survival better. The main focus of this thesis was to analyze implementation of therapeutic hypothermia in Finnish intensive care units (ICU) and its impact on survival, impact of strict glucose control on the survival of postresuscitation patients, incidence of postresuscitation myocardial depression during therapeutic hypothermia and usefulness of serum NSE concentration for prognostication. Patients and methods Implementation of therapeutic hypothermia and survival of postresuscitation patients in ICUs in Finland was analyzed retrospectively using data from the Finnish Intensive Care Consortium quality database. Impact of glucose control on survival of postresuscitation patients was studied in a randomized controlled study of patients treated with therapeutic hypothermia (24 hours at 33°C) in HUCH ICUs (n = 90). The study patients were randomized to strict (4 6 mmol/l) or moderate (6 8 mmol/l) glucose control for the first 48 hours. The incidence of myocardial depression was studied in a retrospective analysis of hemodynamic data from clinical information system database of 120 postresuscitation patients treated with therapeutic hypothermia (24 hours at 33°C) in HUCH ICUs. Usefulness of serum NSE and some other factors as prognostic tools were analyzed retrospectively from laboratory database of 90 postresuscitation patients treated with ­therapeutic hypothermia (24 hours at 33°C) in HUCH ICUs. Results Therapeutic hypothermia was implemented widely in Finnish ICUs in a few years after international guidelines were published in 2003. In the same time, mortality of postresuscitation patients treated in ICUs decreased. Mortality or serum NSE concentration did not differ between patients treated with strict or moderate glucose control. However, strict glucose control increased risk of hypoglycemia. Myocardial depression, manifesting as low cardiac output (CI less than 1.5 l/min/m2), was ­observed during the first 12 hours in two thirds of patients monitored with pulmonary artery catheter. Other hemodynamic parametres did not differ. Serum NSE concentration at 48 hours after cardiac arrest and decreasing concentration at that time point correlated with neurologic outcome, but with 100% specificity, sensitivity was low. Conclusions Therapeutic hypothermia was implemented rapidly in Finnish ICUs, compared with other European countries or USA. This was associated with better outcome, but causality is uncertain. Strict normoglycemia during intensive care of postresuscitation patients is not necessary. The optimal goal for blood glucose level is not known. Myocardial depression manifesting as low cardiac output is common in postresuscitation patients, but difficult to detect without monitoring cardiac output. The impact of ­recognition and treatment of myocardial depression on outcome requires further studies. Serum NSE measured at least 48 hours after resuscitation can be used as a prognostic tool together with other methods.
  • Klemetti, Miira (Helsingin yliopisto, 2015)
    BACKGROUND: Although great advances in diabetes care and obstetrics have been made in the past decades, adverse outcomes remain increased in the pregnancies of women with type 1 diabetes (DM) compared with background populations. AIMS: To analyze the trends in pre-pregnancy body mass index (BMI), glycemic control and blood pressure (BP) levels and their relations to obstetric and perinatal outcomes in women with type 1 DM during 1988-2011. SUBJECTS AND METHODS. A retrospective review of the obstetric records of a population-based cohort of 1094 consecutive type 1 DM patients with a singleton childbirth during 1988-2011 at Helsinki University Hospital (HUH) was carried out. RESULTS: During 1988-2011, the frequencies of BMI 25-29.9 kg/m2 and ≥30 kg/m2 increased from 19% and 2%, respectively, in 1988-1991 to 37% and 10% in 2008-2011. Glycemic control was suboptimal in early pregnancy and deteriorated in late pregnancy. The proportion of women with BP > 130/80 mmHg during pregnancy increased and the preeclampsia rate remained high (19-34%). In the total cohort, the elective and the total caesarean section (CS) rates decreased from 58% and 74%, respectively, in 1988-1991 to 27% and 66% in 2008-2011. The emergency CS rate increased from 16% in 1988-1991 to 39% in 2008-2011. Deliveries before 37 weeks of gestation increased from 29% in 1988-1991 to 49% in 2008-2011, and deliveries before 32 weeks decreased from 4% in 1988-1991 to 2% in 2008-2011. Among the newborn infants, the rates of fetal macrosomia remained high (27-39%) during 1988-2011. The frequencies of umbilical artery pH <7.15 and <7.05 increased from 4% and 1%, respectively, in 1988-1991 to 18% and 4% in 2008-2011. The frequency of neonatal hypoglycaemia decreased from 66% in 1988-1991 to 55% in 2008-2011. Neonatal intensive care unit (NICU) admissions persisted above 15%. The perinatal mortality rate was 1.8% in the total cohort In the analyses of risk factors, poor glycemic control in early and late pregnancy was associated with delivery before 37 weeks, preeclampsia, fetal macrosomia, and NICU admission. Poor glycemic control in late pregnancy was also associated with fetal acidemia at birth and neonatal hypoglycemia. Early-pregnancy BP >130/80 mmHg predicted delivery before 37 weeks, small-for-gestational age infant, NICU admission, and decreased risk of fetal macrosomia. Early-pregnancy BP ≥140/90 mmHg predicted preeclampsia. Maternal overweight was associated with fetal macrosomia. Proliferative retinopathy predicted preeclampsia and delivery before 37 weeks. Diabetic nephropathy predicted preeclampsia, delivery before 37 weeks, reduced risk of fetal macrosomia and NICU admission. CONCLUSIONS: Pre-pregnancy BMI increased, glycemic control before pregnancy and during the second half of pregnancy deteriorated, and BP levels during pregnancy increased in type 1 DM parturients during 1988-2011. The frequencies of most adverse obstetric and perinatal outcomes either persisted at high levels or increased. The results call for an intensified therapeutic approach in type 1 DM women, both before and during pregnancy.
  • Luomaranta, Anna (Helsingin yliopisto, 2015)
    Risk-stratification is an essential step in planning of the treatment of patients with endometrial carcinoma, as it allows the omission of lymphadenectomy and/or adjuvant treatments in patients who are at low risk for extrauterine spread and have a good prognosis. This thesis consists of three cohort studies and one meta-analysis that were conducted to evaluate the reliability of methods that are currently available for the risk-stratification of endometrial carcinoma, and to develop new methods that might be clinically applicable. Cohort studies were based on a sample of 1166 women who were surgically treated for endometrial carcinoma at the Department of Obstetrics and Gynecology, Helsinki University Hospital, between January 2007 and December 2013. In the first study, previously recognized risk factors for an advanced stage and poor outcome were used to create a calculatory score to predict lymph node and distant metastasis in endometrial carcinoma. The score combining weighted risk factors was: (2 x leukocytosis) + (3 x thrombocytosis) + (7 x elevated CA125) + (4 x preoperative high-risk histology, defined as grade 3 endometrioid or nonendometrioid carcinoma). Depending on the number of risk factors of an individual patient, the score ranged from 0 to 16 points. Using six as the cut-point for positive and negative test results, the area under curve for this total score was 0.823, with 71.6% sensitivity, 75.2% specificity, 25.9% positive predictive value, and 95.7% negative predictive value. In the second study, the reliability of macroscopic pelvic lymph node findings at surgery in predicting para-aortic metastasis was evaluated. Lymph nodes were considered grossly positive based on size and morphology. In patients who underwent comprehensive lymphadenectomy (n = 117), grossly positive pelvic nodes predicted para-aortic metastasis with a sensitivity of 52.4% and specificity of 93.8%. The positive and negative likelihood ratios were 8.4 and 0.51, respectively. The whole sample of 854 patients was employed for Bayesian calculations. Grossly positive pelvic nodes at surgery predicted para-aortic metastasis with a negative predictive value of 99.7% in patients with superficial grade 1-2 endometrioid carcinomas and 98.0% in patients with deeply invasive grade 1-2 endometrioid carcinomas. For patients with grade 3 endometrioid and nonendometrioid carcinomas, negative predictive values were 97.3% and 92.2%, respectively. The value was 98.4% for all 854 patients. The third study compared two surgical treatment strategies: 1) routine pelvic lymphadenectomy, and 2) selective pelvic lymphadenectomy for women with high-risk carcinomas according to preoperative histology and magnetic resonance imaging. The combination of preoperative histology and magnetic resonance imaging detected high-risk carcinomas with a sensitivity of 85.7%, specificity of 75.0%, positive predictive value of 74.4%, and negative predictive value of 86.1%. The area under curve was 0.804. In the routine lymphadenectomy algorithm, 54.1% of lymphadenectomies were performed in patients with low-risk carcinoma. In the selective lymphadenectomy algorithm, 14.3% of patients with high-risk carcinoma did not receive lymphadenectomy. Missed positive pelvic nodes were estimated to occur in 2.1% of patients in the selective lymphadenectomy strategy. Similarly, the estimated risk for isolated para-aortic metastasis was 2.1%, regardless of treatment strategy. In conclusion, the risk-scoring model that was developed may provide a cost-effective approach to the risk-stratification of endometrial carcinoma, as it allows prediction of high-risk cases prior to surgery without advanced technology. Selective para-aortic lymphadenectomy, based on gross findings of pelvic nodes, is feasible for patients with grade 1-2 endometrioid carcinomas, regardless of the depth of myometrial invasion. Similarly, gross findings of pelvic nodes can be used to evaluate the need for paraaortic lymphadenectomy in the strategy of routine pelvic lymphadenectomy. The combination of preoperative histology and magnetic resonance imaging is moderately sensitive and specific in detecting high-risk endometrial carcinomas. However, the clinical utility of the method is hampered by the relatively high proportion of high-risk cases that remain unrecognized preoperatively. Considering the poor-to-moderate sensitivity of magnetic resonance imaging in detecting high-risk features of endometrial carcinoma, patients with negative findings may not safely forego lymphadenectomy unless the findings are confirmed by a backup method. The high specificities allow targeting of staging procedures by magnetic resonance imaging alone in patients with positive findings.
  • Joensuu, Emmi (Helsingin yliopisto, 2015)
    Cancer usually arises through mutational changes in the genome but also epigenetic changes can contribute to tumorigenesis. In this research we studied both sporadically occurring and familial colorectal, endometrial and gastric tumors. Sporadic tumors were divided into separate categories depending on the microsatellite instability status of the tumor. In addition to sporadic tumors we studied tumors from patients with different cancer syndromes: Lynch syndrome, Familial colorectal cancer type X and Familial site-specific endometrial cancer. Lynch syndrome patients have a predisposing germline mutation in one of the mismatch repair genes (MLH1, MSH2 or MSH6) and the tumors are typically microsatellite unstable. Despite the extensive research efforts, the genetic or epigenetic background of the other studied syndromes is not known and remains to be molecularly characterized. We therefore explored the possible epigenetic basis of cancer susceptibility in these syndromes. First we studied the promoter methylation of 24 established tumor suppressor genes. Hypermethylation patterns were found to be characteristic of each tissue and diversely dependent on the microsatellite instability status of the tumor, or family category. The CpG island methylator phenotype (CIMP) in which multiple loci are silenced by promoter methylation, was most evident in sporadic microsatellite unstable tumors (P less than 0.001) and was present in 38% of all of the studied colorectal, 19% of endometrial and 29% of gastric tumors. In these tumors the CIMP phenotype can contribute to the genomic instability and the progression of cancer. In addition, despite being microsatellite stable, 50% of Familial colorectal cancer type X tumors displayed the CIMP phenotype. Our results of global hypomethylation confirm that tumors have significantly lower methylation levels compared to normal tissues in most of the studied patient groups (P less than 0.05) and that the hypomethylation levels depend significantly on the microsatellite instability status of the tumors (P = 0.042 for colorectal and P = 0.018 for gastric tumors). The significant decrease in the methylation levels, observed especially in the normal tissues of Familial colorectal cancer type X patients, could function as a premalignant field defect, where a large area of tissue is affected by carcinogenic alteration, and hence promote cancer development by facilitating the accumulation of other lesions such as genetic mutations or other epigenetic changes in the affected areas. After the characterization of different DNA methylation aberrations in distinct tumor categories, we studied the possible mechanisms behind the observed methylation changes. We evaluated the association of the expression of DNA methyltransferases DNMT1 and DNMT3B and histone methyltransferase EZH2 with CIMP+ phenotype and global hypomethylation patterns. Compared to the normal tissues, all the studied methyltransferases were significantly overexpressed in colorectal tumors (P less than 0.001) and DNMT3B also in endometrial tumors (P less than 0.001). EZH2 overexpression was shown to associate with CIMP+ phenotype especially in sporadic colorectal tumors and the finding was statistically significant (P = 0.003). The overall aim of this research was to elucidate epigenetic mechanisms in cancer, including cancers of different organs and also different familial cancers. Available information on the epigenetic events of cancers is increasing and although the topic is under continuous study, our understanding of it is still limited. New knowledge in the field can increase the understanding of the basic tumorigenic mechanisms and thereby facilitate more specific and earlier diagnosis and treatment of different types of cancer. Also the potential reversibility of epigenetic states offers interesting possibilities for drug development.
  • Ropponen, Jussi (Helsingin yliopisto, 2015)
    Chronic lung allograft dysfunction (CLAD) is the major life-limiting factor after lung transplantation and bronchiolitis obliterans syndrome (BOS) is the most common subtype and best-characterized form of CLAD. Pathologically, BOS presents as obliterative bronchiolitis (OB) and it is characterized by peribronchial inflammation, epithelial damage, and obliteration of small and medium-sized bronchioli by fibrotic plaques. BOS is the leading cause mortality after the first post-operative year. In this study, we hypothesized that inhibiting innate immune activation through different pathways influences the development of experimental OB. To test our hypothesis, we investigated different factors and pathways leading to experimental OB using both rat and mouse heterotopic tracheal allograft models. In the presence of alloantigens, early ischemic injury induced both innate and adaptive immune responses followed by Th17 activation and afterwards by a sustained Th1 immune response. This was accompanied by infiltration of the allograft with proinflammatory effector cells and lead to progressive fibroproliferation and total tracheal occlusion. Interestingly, recipient treatment with simvastatin, a cholesterol-lowering drug with lipid-independent immunomodulatory properties, enhanced early epithelial recovery after transplantation in the allografts. It also inhibited the infiltration of inflammatory cells and the expression of lymphocyte chemokines and proinflammatory cytokine mRNA. Most importantly, simvastatin inhibited the development of experimental OB in the absence of other immunosuppression. The cellular responses to hypoxia are regulated by transcription factors called hypoxia inducible factors (HIFs). HIF-1 is a principle regulator of hypoxic adaptation. In this study, we found that continuous HIF-1 expression in myeloid cells improved epithelial recovery, reduced inflammatory cell accumulation, and increased regulatory FoxP3 mRNA expression in mouse tracheal allografts. Importantly, these effects led to better preservation of tracheal epithelium and a decrease in the development of experimental OB suggesting a protective role of HIF-1 in this constellation.
  • Koivunen, Riku-Jaakko (Helsingin yliopisto, 2015)
    Intracerebral hemorrhage (ICH) is a devastating form of stroke. Its common risk factors include hypertension and smoking, but different underlying causes are numerous. Knowledge regarding clinical characteristics and outcome of young ICH patients, encompassing 10% of all ICH patients, is limited. The aims of this study were to define the risk factors, etiologic distribution, clinical picture, medical complications suffered, and prognosis of ICH at young age. We collected detailed clinical, radiological, mortality and follow-up data on all consecutive patients between 16 and 49 years of age with first-ever ICH treated at the Helsinki University Hospital (HUH) between 2000 and 2010. Results concerning the early course of ICH were compared to a series of ICH patients aged >49 years treated in HUH between 2005 and 2010. Median age was 42 years (interquartile range 34-47) and males comprised 59.5% of the 336 patients included. Annual incidence of ICH was 4.9 (95% confidence interval 4.5-5.3) per 100 000. The most prevalent risk factors were hypertension (29.8%) and smoking (22.3%). Compared to older ICH patients (n=921) hypertensive microangiopathy was less common (25.0% vs. 34.3%, P=0.002) and structural lesions more common (25.0% vs. 4.9%, P<0.001) assumed etiologies of ICH. The cause remained elusive in 32.1% of all young patients, and in 22.5% of those who underwent MRI and any angiography (n=89, P=0.023). Three-month mortality rate was lower among young patients compared to older ones, (17.0% vs. 32.7%, p<0.001). Hematoma volumes were similar across all ages (p=0.324) and it independently predicted mortality in older patients, but not in the young. More severe stroke initially, measured by the National Institutes of Health Stroke Scale (NIHSS) score, infratentorial hematoma location, hydrocephalus, herniation, and multiple hemorrhages associated with increased 3-month mortality. When adjusted for these factors as well as demographics, ICH volume, and the underlying cause, we found that surgical evacuation was associated with lower mortality (odds ratio 0.06; 95% confidence interval 0.02-0.21, P<0.001). In propensity-score matched analysis, case-fatality rates were three-fold in those treated conservatively (27.5% vs. 7.8%, P<0.001). The most common medical complications included hyperglycemia (51%), hyponatremia (45%), hypopotassemia (32%), and infections (28%). Hyperglycemia was the only single complication independently associated with increased mortality (5.90, 2.25-15.48, P<0.001). However, three or more concomitant complications also associated with increased mortality (7.76, 1.42-42.49, P=0.018). Among the 268 one-month survivors, 1-year survival was 98.1% (95% confidence interval 96.2-100%), 5-year survival 93.2% (89.3-97.1%), and 10-year survival 88.8% (84.9-92.7%), with male gender (3.36, 1.28-8.80, P=0.014) and diabetes (2.64, 1.01-6.89, P=0.047) being associated with mortality. Unfavorable outcome (modified Rankin Scale score 2-5) emerged in 49%, and was independently predicted by higher age (1.09 per one year, 1.03-1.15, P=0.002) stroke severity (1.17 per one NIHSS score point, 1.08-1.27, P<0.001), and intraventricular extension of hemorrhage (3.26, 1.11-9.55, P=0.031). PSD was present among one out of four survivors of ICH at young age. Since only one out of ten currently used antidepressants, treatment of depression appears as an unmet need in young ICH survivors. In summary, prevention and treatment of cardiovascular risk factors are vital in ICH prevention among young adults. Comprehensive diagnostic work-up and imaging are essential in identifying the underlying cause of ICH. The young seem to survive ICH better than the elderly, particularly if surgical hematoma evacuation is pursued. A holistic approach to prevent and treat associated complications, specifically hyperglycemia, is vital in regard of survival. Only half of the survivors reach favorable functional outcome. Therefore, more effective measures of rehabilitation and mental health must be developed to improve the quality of life of this patient population.
  • Hemminki, Otto (Helsingin yliopisto, 2015)
    In 2012 WHO announced cancer as the leading cause of death. Every day 20 000 people die due to cancer, and the rate is estimated to double before year 2030. While treatments have progressed, there are still few good treatment options for advanced cancer. Thus, there is an urgent need for new treatments. Immunotherapy with gene modified oncolytic adenoviruses provides novel promising means of treating cancer. These treatments incorporate two basic concepts. Firstly, adenoviruses are modified so that they replicate only in cancer cells, which makes the treatments safer. Secondly, the virus induced cancer cell oncolysis elicits a danger signal that awakens the immune system to fight the cancer. Viruses can be further armed with different genes that can stimulate the immune system even more. Most of these oncolytic viruses are based on adenovirus serotype 5, as indicated in thousands of publications. However, the primary receptor for serotype 5 is down-regulated in advanced cancer. On the contrary, adenovirus serotype 3 receptor is known to be abundant in advanced cancer making it an interesting subject of research. While a different serotype per see offers an alternative immune response, serotype 3 incorporates also other interesting features that might further potentiate its utility. Our first goal was to create serotype 3 based oncolytic adenoviruses for the treatment of human cancer. The goal was achieved, making this virus, to our knowledge, the first non- adenovirus 5 based oncolytic adenovirus in the world used in humans. The publications, study I and II, are now part of this thesis. The virus was designed to have a human telomerase reverse transcriptase (hTERT) promoter diverting the replication of the virus into cancer cells. This virus, Ad3-hTERT-E1A, was successfully cloned, rescued and produced in large scale, which was followed by rigorous preclinical testing of the virus. Rigorous preclinical testing of the virus followed. Several in vitro and in vivo experiments were performed, including sequencing, qPCR, electron microscopy and neutralizing antibody assays, while the most convincing data was gained from the cell cultures and the animal models. We found the serotype 3 effective in all major cancer types in vitro. In vivo, the serotype 3 virus was found at least as potent as serotype 5 based control viruses in several murine models of human cancer. Before clinical treatments, biodistribution and toxicity experiments were performed. In toxicity studies, adenovirus 3 was found less toxic than the serotype 5 based control viruses in an immune competent murine model. The histology of all major organs and basic blood values were analyzed. The preclinical data suggested strong efficacy with good safety. In study II, we publish the data of the first 25 patients treated with the Ad3-hTERT-E1A virus. All patients had advanced solid tumors refractory to standard therapies. Th e safety of the treatment was good with up to 4x10 12 virus particles given intravenously and/or intratumorally. Overall, all patients experienced mild (grade 1-2) self-limiting flu-like adverse events. No severe adverse events were noted attributable to the treatments. After treatment, many patients showed signs of efficacy. Of the 15 patients with elevated tumor markers before the treatment, 73% responded with a decrease or no change in the markers. Even a few complete responses were reported, while some patients also showed a clear decrease in the tumor mass according to imaging. Also the clinical data suggested strong efficacy with good safety, proposing a need for a randomized study. Our next goal was to evaluate better ways in finding treatment responders, as size based computed tomography (CT) is known to be suboptimal in evaluating immunotherapeutics where initial swelling of the tumor due to the immune response is common. In study III, we examined the ability of magnetic resonance imaging (MRI) and spectroscopy (MRS) in immunocompetent Syrian hamsters. T2 weighed MRI seemed encouraging in finding responding hamsters as soon as two days after treatment. Similar findings were noted with a patient responding to oncolytic treatments. MRS of taurine, choline and unsaturated fatty acids were found to be promising metabolites when evaluating responders after oncolytic immunotherapy. These results propose MRI and MRS as potential methods in evaluating responding patients. T2 weighed MRI is already widely used in the clinics, thus a clinical trial should be easy to implement. In study IV, we evaluated the first 16 patients treated with a quadruple modified oncolytic serotype 5 adenovirus. Th e fiber knob of this virus is from serotype 3, while the virus also produces an immunostimulatory GM-CSF molecule. Th e two other modifications restrict the replication to cancer cells. The safety profile of the virus resembled that of the oncolytic serotype 3 virus, and also numerous signs of effi cacy were noted. Immunological studies indicated activation of the immune system in responding patients. Rationale for a randomized study exists also for this virus.
  • Kriikku, Pirkko (Helsingin yliopisto, 2015)
    Driving under the influence of drugs (DUID) can adversely affect driving skills in numerous ways and put lives at risk. Legal approaches to DUID vary considerably from country to country, even within Europe, and, in the last decades the emergence of new psychoactive substances (NPS) has further complicated the scene. DUID is an unlawful act if the substance taken is banned or impairs driving. The latter is hard to define and prove, putting pressure on governments to ban NPS as quickly as possible in order to protect the public by facilitating enforcement of DUID laws. However, banning requires knowledge on several aspects of NPS such as prevalence, pharmacology, abuse potential and toxicity. Up-to-date, evidence-based information on NPS is needed by legislators, toxicologists, clinicians, and other health care professionals. Such information would enable potential drug users and the public to be more aware of the risks associated with illicit use of NPS. This study aimed to add to the knowledge of the NPS most relevant in Finland. In this thesis, the prevalence, blood concentrations in drivers and in post-mortem cases, and demographic details of 3,4-methylenedioxypyrovalerone (MDPV) and desoxypipradrol (2-DPMP), were investigated. Changes in prevalence and other characteristics of MDPV were monitored over a time span covering a period before its banning as well as a few years after banning. Phenazepam, a Russian therapeutic benzodiazepine now illegal in Finland, was studied by examining both DUID and post-mortem cases. The use by apprehended drivers of pregabalin, a prescription anticonvulsant with therapeutic indications for neuropathic pain, partial seizures and generalised anxiety disorder, was also studied. The results of this study showed that DUID cases provide a valuable source of information on NPS prevalence and user profiles. However, little specific information could be gained about the impact on driving performance and health risks of NPS mainly due to the fact that NPS were usually used together with a spectrum of other psychoactive substances. It could, however, be concluded that all of the studied NPS were frequently detected in the samples collected from apprehended drivers and, in the case of MDPV, the prevalence changed with time. The number of MDPV-positive cases among apprehended drivers decreased by 51.1% after the drug was banned. The concentrations of NPS found in DUID cases were within the range anticipated to produce significant adverse effects on driving performance, or, in some cases, in the range found in post-mortem cases where the drug may have contributed to the fatality. The presence of the medicinal drug, pregabalin, was found to be connected to abuse rather than appropriate medical use since it was in most cases found in concentrations higher than those recommended for therapeutic use and together with illegal drugs such as amphetamine or cannabis. In post-mortem cases positive for MDPV, the prevalence of suicide was much greater than in fatalities related to other drugs. Three independent registries, namely the DUID toxicology data, the post-mortem toxicology database, and court documents, were examined to gain novel information on the characteristics of NPS use and those abusing them. The large number of cases studied produced information on concentration ranges associated with abuse of the studied substances.
  • Mäkinen, Mauno (Helsingin yliopisto, 2015)
    The psychological influence of obesity on health is less clear than the physical impacts. Further follow-up studies are needed to examine causality/directionality. To investigate psychiatric disorders in excess-weight adolescents, more studies with diagnostic interviews are required, because the results of previous results have been contradictory, probably reflecting methodological differences. The aim of the study presented in this dissertation was to examine psychological well-being and psychiatric disorders linked to overweight and obesity in a general mid-adolescent population. The study was performed from 2003 to 2005, involving girls and boys aged approximately 14.5 years attending secondary schools in Helsinki. The students completed self-assessments surveying self-esteem (RSES), their thoughts and ideas concerning eating behaviors (EDI), as well as their lifestyle. Both measured and self-reported weights and heights were recorded (Study I sample: 650 girls, 693 boys; Study II sample: 614 girls, 651 boys). A subgroup of adolescents (Study III subsample: 86 girls, 96 boys) was diagnosed by an adolescent psychiatrist using a structured diagnostic instrument (K-SADS-PL). Furthermore, a subgroup (Study IV follow-up subsample: 78 girls, 88 boys) was followed up for one year and completed a questionnaire assessing the self-image (OSIQ-R) both at baseline and on follow-up. In summary, psychological well-being was good in most of the overweight and obese adolescents. However, the excess-weight adolescents significantly more often revealed body dissatisfaction and other symptoms related to eating disorders (p < 0.001) and abnormal dietary behavior (p < 0.001) than their normal-weight peers. Adolescents with abnormal eating behavior reported significantly greater body dissatisfaction than those with normal eating behavior (p < 0.001). The excess-weight adolescents significantly more seldom reported experiences of dating than their normal-weight peers (p < 0.001). The boys with excess weight exercised significantly more seldom than their normal-weight peers (p < 0.001). The prevalence of lifetime and current psychiatric disorders did not significantly differ between the excess-weight and normal-weight adolescents. The prevalence of one or more current psychiatric disorders was 13.2% among adolescents with excess-weight. The self-image of girls with normal weight developed intensively during the one-year follow-up period compared to girls with excess weight (p < 0.024). In component scales, the difference in change scores was largest in sexuality (p = 0.018) and vocational attitudes (p = 0.041).