Lääketieteellinen tiedekunta

 

Recent Submissions

  • Salmenkari, Hanne (Helsingin yliopisto, 2019)
    The intestine is a major site of immune activity, and disturbances in the balance of proinflammatory and anti-inflammatory signals can lead to difficult and chronic diseases, like inflammatory bowel diseases, manifesting in uncontrolled inflammation in intestine. Local intestinal renin-angiotensin system (RAS) and glucocorticoid synthesis are recently uncovered complex mechanisms participating in the pathophysiology of intestinal diseases. These systems can offer new therapy options, either by repurposing well-known drugs like angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers or by novel innovations like mesenchymal stromal cell therapy. The aim of this thesis was to investigate intestinal RAS and glucocorticoid production in intestinal inflammation and examine potential treatments with the focus on these two systems. RAS and glucocorticoid production and their possible interactions in intestine were characterized in a dextran sodium sulfate (DSS)-induced experimental colitis model using in vitro stimulations and inhibition of RAS in vivo. Glucocorticoid synthesis and ACE shedding were investigated as the release of corticosterone and ACE protein from live tissue to incubation media in vitro. The effects of ACE inhibitor, captopril, and ACE-inhibiting milk-derived bioactive tripeptide, Ile-Pro-Pro, were examined on intestinal RAS and glucocorticoid synthesis. ACE inhibitor, enalapril, and angiotensin II receptor blocker, losartan, were tested alone and in combination in alleviation of colitis. Finally, freshly cultivated and cryopreserved platelet-lysate expanded mesenchymal stromal cells were compared and their feasibility was examined in the treatment of colitis. Enalapril and losartan were effective at alleviating colitis and lessening inflammation on their own but were without synergistic effects, supporting their potential to be investigated in clinical trials. MSC treatments proved feasible and without adverse effects, and freshly cultivated MSC treatments had a modest anti-inflammatory effect reflected by reduction in proinflammatory cytokine levels. We found a specific induction of ACE ectodomain shedding in distal colon, the most affected region in DSS-induced colitis, and in proximal colon following a high DSS dose. ACE shedding could be downregulated by cryopreserved MSCs and an ACE-inhibiting tripeptide Ile-Pro-Pro treatment in vivo. These data imply that cell-surface ACE levels are actively regulated in intestinal inflammation, which could be a feedback mechanism to reduce the proinflammatory angiotensin II (Ang II) signaling. Ang II induced glucocorticoid production in small intestine incubations in vitro, thus implying of an anti-inflammatory property in Ang II signaling. We suggest that Ang II enhances the TNFα-mediated induction of glucocorticoid production during intestinal inflammation. In vitro or in vivo inhibition of Ang II production or signaling did not modulate intestinal glucocorticoid production, although captopril abolished the gene expression of the rate-limiting enzyme of glucocorticoid synthesis, Cyp11b1, in vivo.
  • Kero, Mia (Helsingin yliopisto, 2019)
    One of the leading health challenges worldwide is dementia, the incidence of which is rapidly increasing along with increasing life expectancy. The number of people with dementia is estimated to reach 150 million by 2050. Thus, the estimated financial costs associated will be enormous, and there is tremendous pressure to find better tools for the prevention, early detection and treatments of dementia. The most common neurodegenerative disease is Alzheimer´s disease (AD), covering at least 50% of patients with dementia. Other common dementing diseases include vascular dementia (VaD) (20%), frontotemporal lobar degeneration (FTLD) (10%) and dementia with Lewy bodies (DLB) (5%). In addition, neuropathological studies have suggested some recently identified neurodegenerative entities to be common in the very elderly population. One such entity is hippocampal sclerosis of aging (HS-Aging), which is characterized by neuronal loss in the hippocampal CA1 and subiculum, and TDP-43 -positive inclusions in the hippocampal dentate fascia. The general aim of this thesis project was to investigate the frequency and genetic background of age-associated neurodegenerative diseases, particularly HS-Aging and other TDP-43 proteinopathies, in the Finnish population. In Study I, we determined the prevalence of HS-Aging and the associated neuropathological changes in a population-based sample of very elderly Finns (Vantaa85+ study). In Study II, the associations of previously identified risk variants with HS-Aging were investigated in a combined dataset of Finnish and British population-based cohorts. In Study III, the prevalence of an amyloid precursor protein (APP) mutation, previously shown to be protective against AD, was determined among the oldest old Finns. In the last study, Study IV, we investigated the neuropathological and molecular genetic phenotype of Finnish familial patients with FTLD associated with a rare tumor, dysplastic gangliocytoma. HS-Aging was detected in 16% of Finns aged over 85 years. HS-Aging without any other comorbid neuropathologies was seen in only one individual (2% of cases). 51% of subjects with HS-Aging exhibited a bilateral disease, indicating that pathological sections should be taken from both hippocampi for neuropathological diagnostics. Dementia and TDP-43-, p62- and Tau-positive granular cell inclusions were strongly associated (p< 0.001) with HS-Aging (I). The population -representative cohorts confirmed polymorphisms in GRN and TMEM106 to be genetic risk factors for HS-Aging and accumulation of TDP-43 positive inclusions in hippocampus (II). The protective APP mutation (A673T) was detected in only one very aged female (0.19%) subject. This individual exhibited HS-Aging, but no AD pathology, indicating that this mutation probably protects against AD changes (III). The familial FTLD was characterized neuropathologically by abundant hippocampal and cortical TDP-43- and cerebellar p62-pathology, and it was shown to be caused by a hexanucleotide repeat expansion mutation in C9orf72. In addition, C9orf72 repeat expansion mutation hypothetically promoted the development of dysplastic gangliocytoma (IV). In conclusion, this study provided new information on the prevalence and genetic background of HS-Aging and other TDP-43-proteinopathies in the Finnish population. Key words: HS-Aging, population-based, oldest old, risk alleles, APP mutation, C9orf72 expansion
  • Jokela, Johanna (Helsingin yliopisto, 2019)
    During the last few decades, the treatment of sialolithiasis and chronic recurrent sialadenitis has shifted more toward a minimally invasive approach. The development of salivary endoscopy (sialendoscopy) has allowed visual access into the salivary duct system to diagnose and treat various duct conditions. Favorable results have been achieved in the treatment of sialolithiasis and duct strictures, and the symptoms of chronic sialadenitis seem to respond to this novel intervention as well. The aim of the present study was to assess the results of sialendoscopy in the treatment of obstructive and chronic sialadenitis, the complications of sialendoscopy, and tolerability of sialendoscopy under local anesthesia (LA). In addition, the health-related quality of life (HRQoL) of sialadenitis patients and the costs of treatment were investigated. We evaluated the medical records of all (n=228) patients who underwent sialendoscopy at the Department of Otorhinolaryngology – Head and Neck Surgery at Helsinki University Hospital (HUS) between January 2011 and December 2013. Using these data, we analyzed the main endoscopic findings and treatment results. To assess the patient experience and compliance in sialendoscopy, 89 LA patients completed a questionnaire designed by the authors; on it, the patients rated their sensations (pain, discomfort, and nervousness) before, during, and after the operation using a scale from “none” to “major”. In the prospective study, 49 patients with chronic recurrent parotitis without sialoliths were collected. They underwent sialendoscopy and were randomized to receive either a concurrent intraductal injection of isotonic saline solution or 125 mg of hydrocortisone (1:1). To evaluate the incidence and nature of complications associated with sialendoscopy, we prospectively recruited 118 patients with 140 sialendoscopies between October 2015 and December 2016. Patient data, treatment failures, and complications were recorded in a database and analyzed. In the fifth study, all patients (n=260) who had a sialendoscopy at our institution between January 2014 and May 2016 were identified from a surgical database, and the direct hospital costs were retrospectively evaluated from one year before to one year after the sialendoscopy. In addition, the 15D health-related quality of life (15D HRQoL) questionnaire and a survey exploring the use of health care services during the preceding three months were mailed to the patients preoperatively and at 3 and 12 months postoperatively. The sialoliths were successfully removed in a majority of patients, but removal was possible with the endoscopic technique only in a minority. The symptoms resolved or improved in most patients after successful sialolith removal or stricture dilatation. Improvement was also seen in patients with inflammatory changes, but the symptoms relapsed quite often in this group. A single-dose steroid injection concomitant to sialendoscopy provided no additional benefit for the symptoms of chronic recurrent parotitis in this study. In most cases, both diagnostic and interventional sialendoscopy were well tolerated under LA or under local anesthesia with sedation (LAS), with reasonably low patient-reported discomfort and pain. The complications of sialendoscopy were usually related to interventional procedures, and infection was the most common complication. Treatment costs were higher in sialolithiasis patients than in patients with other diagnoses. In sialolithiasis patients, the improvement of HRQoL was noticed at three months postoperatively. In conclusion, according to this study, sialolithiasis patients benefit from the sialendoscopic intervention but combined techniques are often needed. Symptoms of chronic recurrent parotitis seem to improve after sialendoscopy, but total resolution of symptoms remains rare. Sialendoscopy is a safe and well-tolerated procedure, but not free of complications. It improves HRQoL, at least in patients with sialolithiasis in a short-term fashion.
  • Salonius, Eve (Helsingin yliopisto, 2019)
    Articular cartilage is highly specialized tissue that covers the ends of bones in joints. The intrinsic repair capacity of cartilage is poor due to the avascular nature of the tissue. The prevalence of cartilage defects is expected to increase, and if untreated, they may lead to premature osteoarthritis, the world’s leading joint disease. Surgical cartilage repair techniques aim at improving joint function and ceasing the degeneration progress. Implantable biomaterial scaffolds have been developed to create a supporting structure for regenerating cartilage tissue. Despite promising short term results, a material that is able to support the formation of durable hyaline cartilage is yet to be developed. The feasibility of a novel composite material rhCo-PLA that combines recombinant human type II collagen and poly(L/D)lactide felt was tested in a porcine model together with autologous chondrocytes. The scaffold resulted in repair tissue similar to a clinically used commercial collagen membrane. Subchondral bone lesions beneath the repair site developed in all study groups but the novel scaffold resulted in fewer bone defects than the commercial control. Damaged subchondral bone might require filler material in order to restore the height of the cartilage surface and joint congruence. The repair of deep osteochondral defects with porous poly-lactic-co-glycolic acid (PLGA) scaffolds and scaffolds combining PLGA with bioactive glass (BG) fibers (PLGA-BGf) was studied in a lapine model. PLGA resulted in bone volume fraction similar to that of spontaneous healing. PLGA-BGf worsened the repair and the defects were filled with loose connective tissue instead of bone. Commercial controls, beta-tricalcium phosphate and BG granules, resulted in extensive bone formation. Animal models are used in the development of new treatment options. In order to improve the effectiveness and ethical use of the equine model in cartilage repair, spontaneous repair capacity of equine carpal cartilage was evaluated to find the critical lesion size beyond which spontaneous repair does not occur. We found out that 2 mm is the critical lesion size for chondral lesions and 4 mm for osteochondral defects. Autologous chondrocytes have been used in cartilage repair for more than 20 years but their amount is limited and they require two separate surgeries. Bone marrow-derived human mesenchymal stem cells can be used as an alternative cell source. Predifferentiation of these cells in rhCo-PLA scaffolds manufactured either with type II or type III collagen was evaluated in vitro. Chondrogenic differentiation resulted in chondrocyte hypertrophy at an early phase of cell culture. The different collagen types in rhCo-PLA scaffolds did not affect the outcomes. All animal models used in this study demonstrated that subchondral bone defects are associated with cartilage defects and repair procedures. This emphasizes the fact that the synovial joint is a functional unit comprised of several tissues and the challenge of cartilage repair is further complicated by comorbidities in the adjacent tissues.
  • Kondelin, Johanna (Helsingin yliopisto, 2019)
    Colorectal cancer (CRC) is the third most common cancer and accounts for 10% of all new cancers. Approximately 85% of CRCs are microsatellite stable (MSS) while 15% exhibit microsatellite instability (MSI). Of MSI CRCs, 80% are sporadic cases and 20% associate with Lynch syndrome. MSI results from DNA mismatch repair (MMR) deficiency that leads to the accumulation of a high number of mutations, especially small insertions and deletions (indels) in short repeats called microsatellites. In the coding region, these may lead to premature termination codons and truncated protein products. In MSI CRC, also the point mutation rate is elevated. Genes that provide growth advantage to cells via loss of function mutations in microsatellites are called MSI target genes. Many criteria have been suggested to distinguish these genes from incidentally mutated passengers, one of them being simple mutation frequency. To date, numerous genes have been published as candidate MSI target genes and putative tumor suppressors, often based on their mutation frequency alone, but the functional data remains sparse. On the contrary, only few oncogenes are known in MSI CRC, and they are most often flagged by somatic mutation hot spots. Due to the high mutation frequency in MSI CRC, the challenge of distinguishing driver mutations from passengers is augmented. Therefore, when mutation frequencies are evaluated as evidence for selection in MSI CRC, considering the high background mutation rate is of paramount importance. At the same time, the high mutation count makes these tumors a sensitive system for the study of mutation accumulation and selection. The aim of this study was to identify novel driver genes in MSI CRC and to investigate a potential single marker for MSI. In the first study, we sought to identify novel oncogenes with somatic mutation hot spots. We utilized exome sequencing data from 25 MSI CRCs and respective healthy tissues and identified 15 novel candidate oncogenes with confirmed mutation hot spots. Three of the genes (ZBTB2, PSRC1, and RANBP2) showed mutations also in the validation set of 86 additional MSI CRCs and thus emerged as our top candidate oncogenes. The interactomes of ZBTB2 and PSRC1 were studied with liquid chromatography-mass spectrometry and were found to consist of many proteins previously linked to cancer. An increase in cell proliferation was observed for the CRC-associated form of mutant ZBTB2. Additional functional validation is warranted to confirm the role of these genes in MSI CRC tumorigenesis. In the second study, we exploited the high number of mutations from the exome sequencing data of 24 MSI CRCs and the corresponding normal samples to comprehensively catalogue all indels targeting mononucleotide microsatellites. We developed a new statistical model for the somatic background indel rate in mononucleotide microsatellites. We combined mutation significance from our statistical model with mutation clonality in the validation set of 93 additional MSI CRCs to identify the most likely MSI CRC target genes. Two genes – AASDH and SLC9A8 – emerged as our top novel candidates that to our knowledge had not been implicated in MSI cancers before. Further functional validation is required to confirm the pathological role of these genes in MSI CRC. In the third study, we aimed to identify new cancer genes driven by point mutations in MSI CRC. We utilized exome or whole genome sequencing data from 36 MSI CRCs and with MutSigCV and OncodriveFML algorithms we ranked genes based on mutation significance. Two genes – SMARCB1 and STK38L – were selected for further functional validation. A comprehensive interactome analysis revealed enrichment for carbon metabolism in the SMARCB1 binding partners exhibiting altered interaction with the mutant SMARCB1 protein. The mutant STK38L protein in turn exhibited altered interactions with many proteins previously linked to cancer. In a colony formation assay, the SMARCB1 mutant protein increased the formation of drug resistant colonies. Also, in order to continue on our efforts in study I, we identified genes with recurrent somatic mutation hot spots. Seven genes displayed hot spot mutations also in the validation set of 93 additional MSI CRCs, and therefore emerged as our candidates for novel oncogenes in this tumor type. However, additional functional validation is warranted to further understand the role of the genes identified in this study in MSI CRC development. In the fourth study, we examined a 16 T/U mononucleotide microsatellite in the 3’UTR of the EWSR1 gene that was previously reported to show perfect sensitivity and specificity in detecting MSI in colorectal, endometrial, and gastric cancers in two independent populations. We analyzed the repeat with PCR and subsequent fragment analysis in 213 MSI CRCs from two independent populations, 148 MSS CRCs, and the respective normal samples. We found the repeat to be altered in 212/213 (99.5%) MSI CRCs. All the 148 MSS CRCs were wild type for the locus. Therefore, in our data, the repeat showed nearly perfect sensitivity for MSI and thus represents a potential single marker for MSI in CRC. Characterizing the genetic changes underlying cancer development is fundamental in basic cancer research. A profound understanding of cancer biology is a prerequisite for the development of targeted therapies and personalized medicine. In recent years, MSI cancers in particular have shown considerable potential for targeted immunotherapies.
  • Simoila, Laura (Helsingin yliopisto, 2019)
    During the 19th century and beginning of the 20th century the concept of eugenic ideology raised its head. In Finland the law for forced sterilization was accepted in 1934 and government-funded sterilization program took place all over the country. Between the years 1935-1970, approximately 7500 people, mostly women were sterilized according to current sterilization law (Hietala, 2009). Almost half of the sterilized individuals suffered from intellectual disability, but there were also persons with schizophrenia. The position and role of women with schizophrenia and schizoaffective disorder has improved since the times described above, but the road has not been easy. However, both the ongoing de-institutialization, as well as the use of modern antipsychotic medications with less endocrine side-effects has led to an increase in relative fertility and pregnancies of the women with schizophrenia. The purpose of this nationally representative follow-up study was to assess induced abortions and pregnancy-related and delivery-related health outcomes of women with schizophrenia or schizoaffective disorder, as well as to investigate negative perinatal health outcomes and out-of-home placements of their offspring. Using the Care Register for Health Care, Finnish women, born between the years 1965 and 1980 and diagnosed with schizophrenia or schizoaffective disorder were identified during the follow-up period ending 31.12.2013 (n= 5214). For each case, five age- and place of birth-matched controls were obtained from the population Register (n= 25,999). The Medical Birth Register, the Induced Abortion Register, the Register of Congenital Malformations and the Child Welfare Register were used to gather information about mothers and their offspring. The incidence of induced abortions in women with schizophrenia or schizoaffective disorder is similar to that of population controls, but their risk per pregnancy was over two-fold. Women with schizophrenia or schizoaffective disorder were significantly older and more often single at the beginning of the pregnancy. Their body mass index (BMI) before pregnancy was significantly higher and they smoked significantly more often both in the beginning of the pregnancy and after the first trimester. During pregnancy, the risk of pathologic oral glucose test, initiation of insulin, fast fetal growth, premature contractions and hypertension was significantly higher among affected women. Focusing on obstetric complications, the risk of induction of labor, delivery by cesarean section and delivery by elective cesarean section was significantly higher among affected women. The risk of premature birth, low birth weight, low Apgar score at 1 minute, and having a major congenital anomaly to name a few was significantly increased among babies with a mother suffering from schizophrenia or schizoaffective disorder. Children with an affected mother were placed out of home significantly more often than those with a non-affected mother. Among affected mothers, single motherhood and smoking in the beginning of pregnancy but not unwanted perinatal health outcomes of the child increased the risk of out-of-home placement. Schizophrenia and schizoaffective disorder are associated with some risk factors related to pregnancy, as well as with some pregnancy- and delivery-related complications. Maternal schizophrenia and schizoaffective disorder associate with some negative perinatal health outcomes, as well as with out-of-home placements of the offspring. Family planning services,
  • Luoto, Topi (Helsingin yliopisto, 2019)
    Background In children various underlying diseases of the liver parenchyma and vasculature may increase portal pressure and eventually lead to complications of portal hypertension (PH). Clinically significant complications include gastroesophageal varices with the risk of variceal bleeding over time, splenomegaly and hypersplenism. The management and outcomes highly depend on the underlying liver disease. Endoscopic interventions, surgical shunt procedures and liver transplantation (LT) are the main treatment options. During the last few decades the outcomes of patients with pediatric onset PH have improved as management protocols of biliary atresia (BA) and LT have evolved and mesoportal bypass was introduced. Despite these advances the long-term outcomes of pediatric onset PH are insufficiently characterized, as are the incidence of underlying diseases and characteristics of disease progression. Aims The general aim of the thesis was to describe outcomes of patients with pediatric onset PH extending into adulthood. Special emphasis was set on surgical treatment, survival, long-term outcomes, and patient reported health. In addition, characteristics of underlying diseases and possible risk factors for portal vein thrombosis (PVT) and sepsis after pediatric splenectomy were addressed. Patients and methods The thesis contains 4 studies with 4 separate study populations. All patients have been treated in the Helsinki University Children’s Hospital. 1) A retrospective hospital record review was performed on 24 consecutive children with extrahepatic portal vein obstruction (EHPVO) referred for operative treatment during 2002-2010. The mesoportal bypass was constructed using both greater saphenous veins. The mphasis of the study was on long-term graft patency and resolution of PH. 2) A retrospective hospital record review was done on 33 consecutive patients diagnosed with autosomal recessive polycystic kidney disease (ARPKD) during 1980-2011. The focus was on the clinical characteristics and management of ARPKD related liver disease in relation to renal failure. 3) A retrospective hospital record and nationwide registry review was done on 141 consecutive children having undergone splenectomy during 1991-2010, out of these 52 patients (37%) were operated laparocopically. The focus was on septic infections, PVT, and causes of death. Out of the 114 survivors, 66 patients (58%) replied to the structured questionnaire, 64 patients (56%) underwent clinical assessment with ultrasonography of the portal venous system and blood tests. 4) The fourth study population includes 126 consecutive patients treated for pediatric onset PH complicated by gastroesophageal varices during 1972-2013. Overall, 14144 upper gastrointestinal endoscopy reports from 1987-2013 were reviewed to identify patients with the underlying condition. Their outcomes were assessed through hospital records and nationwide registries. A questionnaire was sent to all survivors (n=94) of whom 65 (69%) responded. Main results The mesoportal bypass constructed using the greater saphenous veins proved to be a valuable alternative to the internal jugular vein (IJV) graft, allowing long-term resolution of splenomegaly and hypersplenism, and elimination of gastroesophageal varices. Clinically evident PH developed in half of the long-term ARPKD survivors necessitating endoscopic and/or surgical interventions in 30%. After pediatric splenectomy none of the patients developed PVT and sepsis was associated almost exclusively with an underlying immunodeficiency with a high mortality rate. Overall, the fourth study population (n=126) contained 19 underlying disorders including BA (35%), EHPVO (35%) and ARPKD (7%). During the median follow-up of 15 (range 6 months – 43 years) years patients underwent median 9 (1-74) upper gastrointestinal endoscopies. Esophageal varices were first observed at the median age of 4 (4 months – 18 years) years, 112 (89%) patients underwent median 6 (1-56) sclerotherapy or banding sessions, and 61 (48%) experienced median 2 (range 1-20) variceal bleeding episodes. Forty-eight surgical shunt procedures were performed to 41 (36%) patients and 38% underwent LT. Portal hypertensive biliopathy was diagnosed in 4 patients. LT was necessary due to hepatopulmonary syndrome in two patients, hepatic encephalopathy in two patients and for one patient due to hepatorenal syndrome. The overall survival was 75% and the median age at death was 9 (6 months – 29 years) years. None of the deaths were related to variceal bleeding and all EHPVO patients survived. The patient reported perception of health on a scale of 1-10 was 9 (range 4-10), and 86% reported no current symptoms attributable to esophageal varices. Conclusions Various heterogenous diseases cause PH in children, BA and EHPVO being the most common underlying diseases accounting for 2/3 of the patients in Finland. The management and outcomes highly depend on the underlying disease. Despite a multimodal interdisciplinary approach with prophylactic endoscopic treatment combined with surgical procedures long-term morbidity remains high and continues in adulthood. Mortality was related to complications of advanced liver disease and its treatment, but not to variceal bleeding. The patient reported health of long-term survivors was good.
  • Hulkkonen, Sina (Helsingin yliopisto, 2019)
    Entrapment neuropathies of the upper extremity, including carpal tunnel syndrome (CTS) and ulnar and radial neuropathies are common in the general population. The most common of these is CTS, the prevalence of which can be up to 5%. These neuropathies cause loss of hand function, disability, sick leaves and high health care costs. Up to two thirds of diagnosed cases are treated surgically. However, their aetiology is multifactorial and is still not fully understood. This study evaluated the incidence rate and the proportion of surgically treated cases of CTS, ulnar nerve entrapment (UNE) and radial neuropathies in the Finnish population, based on data from the Care Register for Health Care on hospitalizations in specialist care, 2007–2016. The risk factors for CTS and UNE were studied in the Northern Finland Birth Cohort 1966 (NFBC1966), whose participants attended a clinical examination in 1997 and gave their written informed consent (N = 8 719). For CTS, occupational exposures were studied in a sub-population of NFBC1966 participants who worked at least three days a week at study baseline in 1997at the age of 31. In the Finnish population, the crude incidence rates (95% confidence interval, CI) per 100 000 person-years between 2007 and 2017 among women and men were 196.5 (194.8–198.2) and 104.8 (103.6–106.0) for CTS, 25.8 (25.2–26.4) and 36.0 (35.2–36.7) for UNE, and 5.7 (5.4–6.0) and 8.5 (8.2–8.9) for radial entrapment neuropathies. Of these, CTS was operated in 62.6% of women and 61.3% of men, UNE in 43.2% of women and 47.2% of men, and radial nerve entrapment in 11.4% of women and 7.7% of men. CTS was more common among women (women : men risk ratio, RR = 1.4), whereas UNE and radial neuropathies were more common among men (men : women RR = 1.4 and 1.5, respectively). In NFBC1966, overweight or obesity, history of regular smoking, and the socio-economic status of farmers or manual workers increased the risk of CTS over follow-up (1997–2016). Of the self-reported occupational exposures, vibration to the hands was associated with double the risk of CTS. Smoking ten or less pack-years before the age of 31 increased the risk of UNE two-fold and smoking more than ten pack-years over five-fold over follow-up. Overweight or obesity, socioeconomic status, or gender did not increase the risk of UNE in the adjusted analyses. Successful prevention of CTS, UNE and radial neuropathies requires better recognition of their risk factors. This study established several risk factors for CTS, and revealed smoking as the most important risk factor for UNE. Keywords: carpal tunnel syndrome, ulnar nerve entrapment, entrapment neuropathy, risk, factors, register study, cohort study
  • Harjunen, Ville Johannes (Helsingin yliopisto, 2019)
    Emotional expressions as manifested in facial movements, voice, and touch are a crucial part of face-to-face interaction. The majority of existing neuroscientific research on emotional expressions concerns the perception of unimodal emotional cues, such as facial emotional expressions. In natural face-to-face interaction, however, emotions are often expressed as compounds of facial, tactile, prosodic, and postural cues. How the brain processes such multimodal emotional information remains poorly understood. The aim of the current dissertation is to investigate how emotional expressions conveyed consecutively via face and touch are integrated in perceptual processing and decision-making. Four studies were conducted to measure event-related brain potentials (ERPs) and autonomic nervous system responses to simulated touches and facial emotional expression stimuli. The first two studies used virtual reality to investigate how a virtual agent’s facial emotional expressions influenced the way the agent’s subsequent touch was perceived (Study I) and whether the receiver’s individual characteristics influenced this visuo-tactile affective modulation (Study II). Touch perception was measured using self-reports, somatosensory-evoked potentials (SEPs), and cardiac orienting responses (ORs), and the individual characteristics were indexed by behavioural inhibition system sensitivity (BIS) and gender. Study III investigated whether receiving a touch influenced the processing of a subsequent emotional face picture presented on the computer screen. Here, face-evoked ERPs, ORs, and facial electromyography were measured. Finally, the Study IV examined whether a virtual agent’s touch and emotional facial expressions influence receivers’ decision-making and offer-related ORs in an economic decision-making game. Additionally, the study examined whether the receivers’ behavioural inhibition/approach system (BAS/BIS) sensitivities and sensitivity to unfair treatment moderated persuasiveness of nonverbal cues. Study I revealed that happy, angry, and sad facial expressions resulted in amplified SEPs around 20–50 ms after touch onset, whereas in later latencies (250–650 ms), the angry facial expression amplified and the happy expression decreased the SEP amplitudes. In Study II, men with high BIS were found to perceive touch from male agents as especially intense if accompanied by happy, angry, of fearful facial expressions, and they showed pronounced cardiac OR to all the touches. Study III demonstrated that receiving a computer-generated touch did not modulate emotional face processing in any of the measured indices. Finally, in Study IV, people were found to accept unfair offers more often if the agent smiled or touched them before making the offer. The touch had a stronger persuasive influence in people with low sensitivity to unfairness and low approach tendency, whereas the effect of facial expressions was moderated by BIS. Altogether, the findings of the dissertation reveal that a sender’s facial emotional expressions modulate subsequent touch perception at a very early stage and that the modulation is based on different emotional information in different temporal stages. In addition, the findings suggest that motivational tendencies and gender influence the manner in which people perceive a sender’s multimodal emotional expressions and make decisions thereafter. These findings are valuable for basic research, but their implications extend also to the development of novel clinical interventions and social virtual reality applications.
  • Pollari, Marjukka (Helsingin yliopisto, 2019)
    Primary testicular lymphoma is a rare and aggressive lymphoma entity presenting in an immune-privileged site of the testis and most commonly representing diffuse large B-cell lymphoma (DLBCL). Due to the rareness of the disease, no randomized clinical trials have been conducted and the currently recognized standard of care is based on retrospective analysis and few phase II trials. During the last years, tumor-related immunity has been the focus of many studies, and the emergence of targeted therapies and checkpoint inhibitors has significantly modulated the field of cancer therapies. The role of distinct tumor-infiltrating immune cell subtypes and their immunophenotypes has not, however, been thoroughly studied in testicular DLBCL (T-DLBCL). The aims of this study were to evaluate the efficacy of different treatment modalities among T-DLBCL patients identified from the pathology databases of three university hospitals in Finland and the Danish lymphoma registry as well as to characterize tumor-infiltrating immune cell subtypes, their phenotypes and distribution in the TME, and to associate the findings with known clinical and biological risk factors and survival in T-DLBCL. The efficacy of different treatment modalities was evaluated by comparing the patient outcomes of altogether 189 Finnish and Danish T-DLBCL patients. Among these patients, intravenously (IV) administered central nervous system (CNS) -targeted chemotherapy and treatment of the contralateral testis translated into significantly longer patient survival, especially among elderly patients. Intrathecally (IT) administered CNS prophylaxis had no effect on the patient outcome, and rituximab seemed to be beneficial among high-risk (International Prognostic Index (IPI) score 3-5) T-DLBCL patients. In our patient material, the overall CNS relapse rate was low, and no differences in the risk of CNS relapse could be observed between patients treated with different treatment modalities. However, the use of IV CNS-targeted chemotherapy significantly improved the systemic control of lymphoma. Tumor-infiltrating immune cell subtypes, their phenotypes and distribution in the TME were studied using gene expression analysis and multiplex immunohistochemistry (mIHC) on tissue microarray (TMA) slides of 60–79 Finnish T-DLBCL patients. We observed that higher expression of 121 T-lymphocyte signature genes enriched for T-lymphocyte markers associated with significantly longer survival of T-DLBCL patients. The association with survival was especially evident among rituximab-treated T-DLBCL patients and could also be seen in an independent cohort of 96 primary DLBCL patients. We observed a great variation in the distribution of distinct tumor-infiltrating lymphocyte (TIL) phenotypes. Higher proportions of CD3+ TILs in general, CD4+ TILs, and CD8+ cytotoxic T-lymphocytes (CTLs) translated into better outcome. Higher proportions of programmed cell death-1 (PD-1) expressing CD4+ TILs and CTLs associated with significantly longer patient survival. Despite the overall favorable prognostic impact of high TIL content, a subpopulation of FoxP3+T-bet+ double-positive regulatory T-cells (Tregs) could be identified to have a significant adverse effect on patient outcome. We were able to show that a large proportion of both tumor-associated macrophages (TAMs) and lymphoma cells expressed programmed cell death ligand 1 (PD-L1), and higher proportions of PD-L1+CD68+ TAMs associated with longer survival. The content of PD-L1+CD68+ TAMs correlated with the content of PD-1+CD4+ TILs and PD-1+ CTLs, and the proportion of PD-L1+CD68- cells did not have an effect on the outcome of T-DLBCL patients. In conclusion, our results support the use of the currently recognized standard of care with anthracycline-based immunochemotherapy and IV CNS-targeted chemotherapy with prophylactic treatment of the contralateral testis as the first-line treatment of patients with T-DLBCL. The results of our biological studies provide novel information on tumor-infiltrating immune cell subtypes, their phenotypes, and their association with survival among patients with T-DLBCL.
  • Rämö, Joel (Helsingin yliopisto, 2019)
    Despite decades of progress in primary prevention and treatment of acute coronary syndromes and strokes, cardiovascular disease (CVD) remains the leading cause of death and loss of disability-adjusted life years in Western countries. In this thesis, we sought to identify risk stratifying factors beyond the traditional measures of body mass index (BMI) and dyslipidemia. In particular, we focused on the role of hepatic steatosis in obesity, and on the family history of patients with hyperlipidemia. We quantified circulating metabolites during an oral glucose tolerance test in BMI-discordant (ΔBMI ≥ 3 kg/m2) monozygotic twin pairs based on the presence of concomitant liver fat discordance. Liver fat -discordant cotwins exhibited greater putatively atherogenic differences in metabolomic parameters across a wide range of molecular classes, including lipoproteins, fatty acids, amino acids and glycoproteins. We also observed several putatively atherogenic differences between liver fat -concordant twin pairs, suggesting that increased BMI without concomitant liver fat accumulation may not be entirely neutral with respect to CVD risk. We performed the first comprehensive genotyping analysis of familial combined hyperlipidemia (FCH), a common familial hyperlipidemia typically characterized by elevations in total cholesterol or triglycerides. We observed rare high-impact variants in the APOE or APOA5 genes in only a few (3%) of hyperlipidemic family members. Almost a third of hyperlipidemic family members had elevated polygenic burden for LDL-C or triglycerides, similar to population samples with comparable lipid levels. Next, we estimated incident CVD risk in an overlapping cohort of hyperlipidemic families. We focused on common familial hyperlipidemias characterized by high LDL cholesterol or triglyceride levels after excluding individuals with monogenic FH. In our study, such familial hyperlipidemias conferred increased coronary artery disease and CVD risk, but the elevation in risk was similar to that observed in population-ascertained hyperlipidemias. Additionally, we observed highly similar lipidomic profiles consisting of 151 circulating lipid species between individuals with familial and population-ascertained hyperlipidemias. Our results add to existing support for hepatic steatosis as a more discerning stratifying CVD risk factor among individuals with increased BMI. Our findings on FCH and familial aggregation of high LDL cholesterol or triglyceride levels suggest that they share similar and overlapping pathophysiology with common population-ascertained hyperlipidemias, and may not confer differential CVD risk.
  • Toivari, Miika (Helsingin yliopisto, 2019)
    The aims of the present study were to identify the characteristics of facial fractures in geriatric patients and to compare them with younger adults. The hypotheses were that the causes and resulting types of facial fractures are different, and that geriatric patients are more severely injured than younger controls. The present study focused on three different patient populations, diagnosed and treated for facial fractures at a level I trauma center and at the Department of Oral and Maxillofacial Diseases, Helsinki University Hospital, Helsinki, Finland. The study included patients with all types of facial fractures (Studies I and II), with a unilateral orbital fracture (Study III), and with a unilateral ZMO fracture (Study IV). The commonest cause of facial fractures in geriatric patients was falling on the ground, whereas younger adults commonly sustained their injuries due to assault (Studies I to IV). Midfacial fractures were significantly more common in geriatric than younger adult patients (Study I). Orbital fractures were significantly more often extensive among geriatric than younger adult patients (Study III). Associated injuries (AIs) in general, multiple AIs, and mortality were significantly more frequent among the elderly when compared to younger controls (Study II). In patients diagnosed with isolated ZMO fractures, AIs in general and traumatic brain injuries (TBI) in particular were significantly more frequent among the geriatric than the younger control group (Study IV). The causes and resulting types of facial injuries differ between geriatric patients and younger adults, and midfacial fractures need to be meticulously excluded in geriatric patients. The frequency and severity of AIs in geriatric facial trauma requires systematic trauma assessment, repeated examination of patient’s condition, and care in collaboration with several specialties.
  • Rakkolainen, Ilmari (Helsingin yliopisto, 2019)
    Severe burn injury is one of the most devastating traumas with its direct tissue destruction, triggering a systemic inflammation and numerous cytokine-mediated alterations of homeostasis. Acute kidney injury (AKI) is a common sequela in severe burns and substantially increases the risk of death. Known risk factors for the development of AKI are the size of the burn area, age, simultaneous inhalation injury, sepsis and use of nephrotoxic antibiotics. Early AKI develops often from a lack of sufficient kidney perfusion due to insufficient circulation or from rhabdomyolysis. Late onset AKI is often part of multiple organ failure (MOF), which is a gradually progressing, poorly manageable state. MOF is characterized by abruption in coagulation, oxygenation of lungs and kidney function. The focus of this thesis was to investigate novel biomarkers of AKI: neutrophil gelatinase-associated lipocalin (NGAL) (I) and N-terminal pro-brain natriuretic peptide (NT-proBNP) (II) in primary diagnostics of AKI. The thesis also investigated the risk factors for AKI development after severe burn injury and factors affecting the outcome (III), as well the need for long-term renal replacement therapy (RRT) after severe burn injury and possible association of burn injury and cause of death (COD) (IV). Studies I and II enrolled 19 consecutive patients treated at Helsinki Burn Centre between March 2013 and September 2014. Plasma NGAL levels elevated over time in the majority of patients. Out of 19 patients, 17 showed elevated plasma NGAL levels (>150 ng/ml). Two patients showed high NGAL levels (>600ng/ml) without AKI. The area under the curve (AUC) was 0.62 in predicting AKI during the first week after a burn injury, whereas serum creatinine (SCr) and cystatin C (CysC) showed notably better diagnostic accuracy. A multivariable regression model showed that the NTproBNP was correlated with the volume of infused fluids and age but found a negative correlation between the body mass index (BMI) and NT-proBNP levels. NT-proBNP increased over time in all patients. The variation between patients was substantial, and even more variation was observed in patients who developed AKI. No association between AKI and high NT-proBNP was discovered. Study III found that 27.3% of patients developed AKI during the intensive care unit (ICU) stay, defined by an absolute SCr value of at least 120 μmol/l (1.4 mg/dl). 11.2% required RRT, and 19.8% of patients succumbed during their hospital stay. AKI patients showed 52.9% mortality compared to 7.4% of non-AKI patients. Age, TBSA%, sepsis and rhabdomyolysis were independent risk factors for AKI. The RRT had no effect on the significantly reduced mortality in AKI patients. AKI was associated with increased mortality, even in minor burns, and mortality increased substantially in major burns. The prognosis of major burns was relatively good without AKI, though the majority of patients developed AKI in major burns (>50% burned TBSA). Age, TBSA%, sepsis and rhabdomyolysis were independent risk factors for AKI. Age, TBSA% and AKI were risk factors for death during an ICU stay. AKI substantially increased the risk of death (OR of 5.97, 95% CI 2.2-16.2). Study IV included 68 burn patients who had received RRT in the Helsinki Burn Centre between November 1988 and December 2015. 52.9% of patients succumbed during their hospital stay, and 32 discharged patients remained for follow-up. The need for RRT subsided before discharge in 81.3% of survivors. 6.3% of survivors needed RRT for over three months. Two patients received RRT constantly for a total of 10.5 and 17 months, respectively. The need for RRT subsided over time in both cases. 35.7% of deaths occurred because of burns, 7.1% because of kidney failure and 57.1% of deaths occurred for any other reason. One patient developed chronic kidney disease (CKD) and succumbed during follow-up. The study showed CKD as a rare event after burn injury and RRT. It remains possible, however, that a prior burn injury may potentially enhance future development of AKI due to other reasons.
  • Aro, Karoliina (Helsingin yliopisto, 2019)
    Nearly all humans acquire a human papillomavirus (HPV) infection during their lifetime. The vast majority of HPV infections regress spontaneously, even the precancerous lesions (intraepithelial neoplasias) of the female genital tract that HPV causes. Precancerous cervical lesions are treated with local excision, because the progressive or regressive nature of an individual lesion remains unknown. These procedures have a 90% initial cure rate but may predispose to preterm birth. Prophylactic HPV vaccines targeting the two most common HPV types in cervical cancer (HPV 16 and 18) have been available for a little over a decade. A near eradication of HPV infections and precancerous lesions has been demonstrated a decade after vaccination in adolescence; however, the full effect of mass vaccination, especially on cancer rates, will only be seen decades later. Characterising the prevaccination era HPV-type distribution can aid the assessment of the effect of vaccinations and refine screening strategies. Our study of 1279 women assessed for abnormal cytology found a distinct, age-related polarisation of HPV types. Histological high-grade cervical disease was diagnosed in 503 women, and two thirds of cases in young women were attributed to HPV16/18, whereas it was only found in one third of women ≥45. Other high-risk types and even HPV negativity were more common than HPV16/18 in the older women. We performed a meta-analysis on the outcomes of untreated cervical intraepithelial neoplasia grade 2 (CIN2). Summary estimates from 36 studies showed the overall regression rate at two years to be 50% and the progression rate 18%. The two-year regression rate was 60% and the progression rate was 11% in a subgroup analysis of women <30 years of age (approximately 1000 women). Overall progression to invasive cancer was rare (0.5%, n=15/3160). In addition, we assessed the performance of a DNA methylation panel (S5 classifier) in predicting progression of untreated histological CIN2 in a prospective cohort study of 149 women (18-30 years of age). S5 was independently able to predict progression even when adjusted for age, initial cytology, cigarette smoking, and HPV16/18 status. Vaginal intraepithelial neoplasia (VAIN) is more uncommon than CIN. Contemporary treatment is mostly laser vaporisation, but recurrence occurs in up to a third. HPV persistence is associated with recurrence. We recruited 30 women with high-grade VAIN into a randomised trial comparing the efficacy of self-administered vaginal immunomodulator imiquimod, laser vaporisation, and expectant management. No progressions were observed during the follow-up, and histological regression rates showed no significant differences between the study arms. HPV clearance, however, was significantly more common in the imiquimod arm (63%) than in the laser arm (11%).
  • Iso-Markku, Paula (Helsingin yliopisto, 2019)
    Physical activity (PA) has been associated with better cognition or decreased dementia incidence in many earlier studies. Since both PA and cognition are, to a large extent, heritable traits, the association found in earlier studies may be confounded by genetic selection. The aim of this thesis study was to ascertain whether midlife PA is associated with late-life dementia mortality and cognition and if objectively measured late-life PA is associated with late-life cognition and whether the possible associations are contributable to genetic factors and childhood shared environment. The thesis study was implemented in the older Finnish Twin Cohort. Vigorous PA and the volume of PA have been reported in questionnaires in 1975 and 1981. Dementia mortality was followed from the time of the questionnaire in 1981 to the end of the year 2011 (n=21,524). All participants over 65 years of age were offered the possibility to participate in a telephone cognition interview. The cognition interview participants born in 1940–1944 were also offered the possibility to participate in accelerometer monitorings. The participation rates for questionnaires in 1975 and 1981, cognition interviews and accelerometer monitorings were high considering the length of the follow-up (89%, 84%, 78% and 54% among twins alive and with an address in Finland). In the accelerometer study, there was a trend toward a slightly selected population regarding better education and healthier lifestyle. Among the 21,524 twins followed for dementia mortality, there were 353 dementia deaths. Long-term vigorous PA was associated with decreased dementia mortality (hazard ratio (HR) in the fully adjusted model 0.60, 95% confidence intervals (CI) 0.39 – 0.93). The volume of PA and long-term quantitative physical inactivity were not significantly associated with dementia mortality. Among 3050 twins aged 65 years and older and who had participated in cognition interviews, 204 had cognitive impairment. Long-term vigorous PA was significantly associated with better cognition (beta estimate 0.91, 95% CI 0.47 – 1.35), belonging to the most inactive quintile in both questionnaire years 1975 and 1981 was inversely associated with cognition, and volume of PA was not significantly associated with cognition. Late-life objectively measured light PA was positively and sedentary behavior inversely associated with late-life cognition, but the effect sizes were small. In analyses comparing twins with their co-twins, the point estimates were quite similar to those found at the individual level but were statistically non-significant. The number of twin pairs discordant for PA and dementia mortality or cognition was very small. The results indicate that midlife vigorous activity is significantly associated with decreased dementia mortality and better late-life cognition, but the associations are likely to be explained in part by genetic factors and childhood shared environment. The association of objectively measured PA and cognition in late-life seems weak and, also, explained in part by genetic factors and childhood shared environment.
  • Santti, Kirsi (Helsingin yliopisto, 2019)
    Desmoid-type fibromatosis, also known as aggressive fibromatosis or desmoid tumors, are very rare neoplasms, accounting for 0.03% of all newly diagnosed neoplasms and less than 3% of all soft tissue tumors. Desmoid tumors occur in different anatomic locations in musculoaponeurotic tissues and may be painful, although they are seldom fatal. Approximately 10% of desmoid tumors are associated with an inherited condition called familial adenomatous polyposis (FAP) while the majority of desmoid tumor patients harbor a somatic mutation in the CTNNB1 gene. Indolent tumors are surveilled; however, progressing and symptomatic desmoid tumors are managed with surgery, radiotherapy, or systemic therapy. Different systemic approaches include non-steroidal anti-inflammatory agents, endocrine therapy, tyrosine kinase inhibitors, and chemotherapy. This thesis evaluated the outcome of oncological treatments at Helsinki University Hospital. We tried to seek novel molecular markers to identify different risk groups. We also aimed to illuminate the underlying pathobiological mechanisms in desmoid tumors. The patients were treated at Helsinki University Hospital between 1987 and 2010 in study I (49 radiotherapies) and until 2011 in studies III (n = 76) and IV (n = 83). The patterns of recurrences after radiotherapy were analyzed using image co-registration. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. were utilized for response evaluation in studies I and II; additionally, World Health Organization (WHO) criteria were used in study II. Study II examined the effect of cyclin-dependent kinase inhibitor ribociclib together with endocrine treatment in a patient with multifocal desmoid tumors and FAP. A tissue microarray was built of the formalin-fixed paraffin-embedded desmoid tumor specimen. The slides were immunohistochemically stained with Ki67, cyclin D1, cyclin A, and estrogen receptor β antibodies. Digitally assisted evaluation of the slides was carried out using Pannoramic Viewer software (3DHistech, Budapest, Hungary). Radiation dose was independently associated with time to progression in patients treated with surgery combined with radiotherapy or radiotherapy alone (hazard ratio 0.71, p = 0.02). Local control rate was 75% at five years. The majority of recurrences after radiotherapy occurred at the margin of radiotherapy target (82%, 9/11), two were in-target (18%, 2/11), but none was out-of-target. Ribociclin, goserelin, and letrozole reduced symptoms and stabilized multiple desmoid tumors in a patient with treatment-resistant multiple desmoid tumors for ten months. High expression of cyclin A predicted poor outcome after surgery (hazard ratio 1.9, p = 0.02) whereas Ki67 or cyclin D1 expression rate did not reach statistical significance. Estrogen receptor β expression level had a positive association with proliferation. This thesis is a comprehensive investigation of a rare disease entity. The results demonstrate that radiotherapy is an effective treatment in desmoid tumors. High cyclin A expression is a novel risk factor for recurrence after surgery.
  • Rainio, Mia (Helsingin yliopisto, 2019)
    The primary therapeutic options in minor biliary injury (BDI) after cholecystectomy are endoscopic sphincterotomy (ES) only or with stenting (EST). Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended agents in prevention post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). The diagnosis is based on plasma or serum amylase analyses. The feasibility of a quicker but rarely used urine trypsinogen-2 (T-2) dipstick method in ERCP unit has not been properly explored.Acute pancreatitis (AP) varies in severity, from mild AP resolving within days to a severe form (SAP) with organ dysfunction (OD). Most ODs develop after hospital admission. Early recognition of these patients would allow the initiation of maximal intensive care. The aims of this study were (I) to explore whether ES or ES with stenting is superior in minor (Amsterdam type A) bile duct leaks, (II) to evaluate if rectal diclofenac has a prophylactic effect in PEP in an ERCP unit with low PEP rate, (III) to explore the urine T-2 dipstick test in detecting PEP, and (IV) to explore whether serum SPINK1, trypsinogens 1 to 3 (T-1, T-3) and a complex of trypsin-2 and α₁-antitrypsin (trypsin-2-AAT), can predict the development of SAP in patients without OD at hospital admission. In this study, all the patients were referred to Helsinki University Hospital (HUH) Abdominal Centre between 2004 and 2018. In study I, 71 ERCP-patients with minor bile leak (Amsterdam type A) and native papillae were grouped into ES group (ES group, n=50) and ES with stenting group (EST group, n=21). In study II, 1,000 ERCP patients with 100 mg rectal diclofenac formed the diclofenac group (DG), and 1,000 patients without rectal diclofenac served as a control group (CG). In study III, 400 ERCP patients with native papilla and without AP were tested with a dipstick test before, and 4 and/or 24 h after ERCP. In study IV, 239 patients admitted to the HUH emergency room due to AP, SPINK1, T-1, T-2 and T-3, and a trypsin-2-AAT, plasma pancreas specific amylase or amylase, creatinine, and C-reactive protein (CRP) were measured 0-12 h after admission to hospital. Study I found no difference in outcomes in the ES and EST groups in the primary healing rate in a high- or low-grade leak. In study II, the incidence of PEP was 2.8% in both DG and CG groups, and there was no difference between the groups in the severity of PEP or in the effect of diclofenac in higher-risk subgroups. In study III, a urine T-2 dipstick test in the diagnosis of PEP was highly accurate when evaluated with abdominal pain symptoms. In study IV, serum levels of SPINK1, T-1, T-2, trypsin-2-AAT, and creatinine correlated on admission with the severity of AP. SPINK1 was the most accurate predictor for development of SAP. In conclusion, ES seems to be equal to ES and stenting in the treatment of Amsterdam type A bile duct leaks. In a centre with a low risk of PEP, rectal diclofenac showed no preventive effect. In diagnostics of pancreatitis, a negative urine T-2 dipstick test rules out PEP 4h after ERCP, while a positive test with abdominal pain symptoms accurately reveals PEP. In assessing AP patients without OD at the time of hospital admission, SPINK1 appears to be a useful predictor of SAP.
  • Carpén, Timo (Helsingin yliopisto, 2019)
    The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been rapidly increasing in recent decades and OPSCC is currently the 12th most common cancer worldwide. Currently in Finland, close to 200 new OPSCCs are diagnosed annually, whereas in the 1990s the annual number of diagnosed cases was approximately 50. The main driver behind this phenomenon is high-risk (HR) human papillomavirus (HPV) that currently comprises more than a half of new OPSCCs in numerous Western countries including Finland. HPV-positive OPSCC differs distinctly in genetic and pathophysiologic profiles from HPV-negative OPSCC. Both HPV-positive and HPV-negative OPSCC are typically diagnosed at an advanced stage and thus require multimodal treatment approaches that often impair quality of life. In addition, the accuracy to detect HPV in tumor samples has remained suboptimal in clinical practice. The recognition of early clinical signs and finding of reliable diagnostic tools are essential to achieve earlier and accurate diagnosis, respectively. In general, the prognosis of HPV-positive OPSCC patients is excellent and thus there is an initiative to de-escalate the management protocol to decrease the incidence of treatment-related side-effects. Instead, the prognosis of patients with HPV-negative OPSCC has remained poor regardless of improvements in treatment strategies. Hence, new prognostic markers are necessary to develop better and personalized treatment strategies to improve patient outcome and avoid a treatment-related reduction in quality of life. We aimed to compare different HPV-detection methods against the standard method i.e. p16 immunohistochemistry (IHC) to increase the accuracy of detecting active HPV from OPSCC samples. In addition, we wanted to better understand the clinical behavior and early signs and symptoms of HPV-positive and HPV-negative OPSCC. We also studied the role of other oncoviruses (Epstein-Barr virus [EBV] and polyomaviruses) in OPSCC and potential prognostic markers including tumor volume, matrix metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 (TIMP-1). In situ hybridization (ISH) for HR HPV E6/E7 mRNA was found to be a superior method to detect active HPV in OPSCC and thus should be considered as an additional method to p16 IHC. The accurate HPV diagnostics is especially essential when considering de-escalated treatment for HPV-positive OPSCC patients. In our study cohort, HPV presented as the only virus that clearly stratified patients into two different disease entities by clinical behavior and prognosis. However, HPV may not be the only viral factor related to OPSCC. EBV, or more precisely EBV-encoded small RNA (EBER), was found to correlate significantly with HPV and the presence EBER was associated with poorer prognosis among HPV-negative patients. Tumor volume showed prognostic significance in both HPV-positive and HPV-negative OPSCC and was superior when compared with the most recent TNM classification. In addition, elevated TIMP-1 serum levels were significantly associated with poor prognosis in HPV-negative OPSCC patients. As a conclusion, both tumor volume and serum levels of TIMP-1 may serve as potential prognostic factors in OPSCC, especially for patients with HPV-negative tumors that typically have a poor prognosis.
  • García Velázquez, Regina (Helsingin yliopisto, 2019)
    Depression is a common and disabling mental disorder. Empirical studies have shown that depressive symptoms vary substantially according to antecedents and outcome variables. Nevertheless, research is most often reduced to symptom counts and clinical settings. One of the limitations is the lack of knowledge about the presentation of individual symptoms and their association with clinically relevant outcomes, such as severe functional impairment. The heterogeneity of the symptoms may be an important source of information for a better understanding of depression. This thesis aims to produce empirical insights on how individual depressive symptoms relate to severe functional impairment in community-based samples. In this doctoral dissertation, we used symptom-level data from two large epidemiologic studies that are representative of the population of the United States: the Collaborative Psychiatric Epidemiology Surveys (CPES), and the National Health and Nutrition Examination Survey (NHANES). Our results suggest that, in terms of statistical fit, sum-scores functioned almost as efficiently as symptom-level modeling in predicting self-rated functional impairment. However, examining symptoms individually offered a more detailed understanding of depression as a syndrome. For instance, symptom-level analyses revealed that age group moderated the associations of three symptoms with severe impairment. According to our results, middle-aged adults were more prone to feel severely impaired by these symptoms, as compared to adults aged 30 and below and in retirement age. The symptoms were depressed mood, self-criticism, and impaired concentration. Additionally, some symptoms did not have a significant association with high functional impairment in a fully adjusted model. This suggests that the association with impairment runs through other symptoms. In general, we found that cognitive-affective symptoms of depression related consistently to severe functional impairment. Among them, self-criticism emerged as particularly informative for its consistent association with high functional impairment across analyses, and for its effect on other symptoms as revealed by cross-sectional direction of dependence analyses. A practical implication of this is that supporting individuals’ self-worth may protect against the development of depressive symptomatology and its corresponding impact on functioning. Our findings motivate considering a wider range of symptoms, both in terms of severity and content, for further understanding the heterogeneity of depression. Similarly, functional impairment as a core component of severity calls for systematic exploration, and for a more refined measurement. A better characterization of the severity of depression as a continuum is fundamental for theoretical developments in psychopathology, and potentially useful for planning more efficient interventions targeting the most disabling, dominant symptoms.
  • Tolska, Hanna Kaisa (Helsingin yliopisto, 2019)
    Studies have shown that acute postoperative pain is still undertreated in many common surgical procedures such as tonsillectomy, as pain may go unnoticed in everyday practice. Recovery after tonsillectomy may be complicated also by post-tonsillectomy hemorrhage (PTH), which can even be life threatening. The aim of this study was to investigate immediate complications after tonsillectomy particularly pain and PTH, and to evaluate the evidence regarding the analgesic effect of systemic analgesics and dexamethasone for post-tonsillectomy pain and whether topical ropivacaine is effective in the prevention of pain. Studies I and II are retrospective chart reviews including 1533 outpatients operated for tonsillectomy over one year in our institution, that analyzed the incidence of PTH in adult patients (Study I) and the incidence of all postoperative complications of pediatric patients (Study II), and their association with perioperatively administered medications. Study III is a systematic review and meta-analysis on analgesics and dexamethasone for the prevention or treatment of post-tonsillectomy pain in adults and adolescents including 29 randomized, double-blind, placebo-controlled studies. Study IV is a prospective double-blind placebo-controlled study on topical ropivacaine applied to tonsillar beds after removal of tonsils for the prevention of post-tonsillectomy pain in 154 adult patients. In retrospective studies, PTH was the most common complication. Incidence of PTH in adults was 14.5%, and in pediatric patients 7.1%. In pediatric patients the overall incidence of unplanned postoperative contacts was 14%, (revisits 10%, re-admission 8%, pain 3%, fever 2.3%, PONV 1%). Paracetamol, nonsteroidal anti-inflammatory agents, dexamethasone or oxycodone were not associated with an increased risk of postoperative complications in adult or in pediatric population. Among pediatric patients, the use of local peritonsillar infiltration of lidocaine with epinephrine was associated with an increased risk of secondary PTH. In the systematic review, the main finding was the scarcity of data and short duration of follow-up in the included studies. Paracetamol, NSAIDs, dexamethasone, gabapentinoids and dextromethorphan had weak to moderate analgesic efficacy on the day of operation, dexamethasone in multiple doses beyond one day. The mean intensity of pain was moderate to severe for 1-2 weeks despite of medication among adult patients in Studies III and IV. In prospective Study IV, topical ropivacaine failed to reduce post-tonsillectomy pain during the first postoperative week but reduced the need for paracetamol-codeine during the second postoperative week (secondary outcome). In conclusion, PTH is a common complication, especially in adults. The use of peritonsillar infiltration of lidocaine with epinephrine was associated with increased risk of secondary PTH among pediatric patients. Systematic review reveled that the evidence on efficacy of analgesics for post-tonsillectomy pain is still minimal due to lack of good quality studies with long enough follow-up. Pain intensity is usually moderate to severe for more than one postoperative week. Single analgesics are not effective enough to provide clinically meaningful reduction of pain intensity, and thus multimodal pain management is needed. Topical ropivacaine failed to reduce post-tonsillectomy pain during the first postoperative week but seemed to modify pain during the second postoperative week.

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