Lääketieteellinen tiedekunta

 

Recent Submissions

  • Paatela, Hanna (Helsingin yliopisto, 2016)
    Dehydroepiandrosterone (DHEA) and its sulfate ester DHEA sulfate (DHEAS) are the most abundant steroid hormones in the circulation. These prohormones, secreted by the adrenal glands, are important precursors of biologically active androgens and estrogens. Adipose tissue is an important site for estrogen synthesis after menopause, when all estrogens are produced from hormone precursors in peripheral tissues. In the circulation, DHEA exists also as fatty acyl esters. These lipophilic derivatives of DHEA are transported by circulating lipoprotein particles. DHEA and high-density lipoprotein (HDL) both improve endothelial function. The aims of the present thesis were to study the role of DHEA fatty acyl esters in the HDL-mediated vasodilation, to study the cellular uptake and metabolism of HDL-associated DHEA fatty acyl esters in endothelial cells, and to investigate the metabolism of DHEAS in female adipose tissue. The role of DHEA fatty acyl esters in HDL-mediated vasodilation was studied in isolated rat arterial rings. DHEA fatty acyl ester-enriched human HDL showed a stronger vasodilatory effect compared to native HDL. This relaxation was mediated by HDL receptor, scavenger receptor class B, type I (SR-BI), and was partly dependent on the function of endothelial nitric oxide synthase. The metabolism of DHEA fatty acyl esters was studied in human endothelial cells. These cells were able to internalize and slowly hydrolyze HDL-associated DHEA fatty acyl esters and to further secrete the liberated free DHEA from the cells. In abdominal subcutaneous and visceral adipose tissue obtained from pre- and postmenopausal women, steroid sulfatase activity was assessed by the conversion of DHEAS to DHEA, and mRNA expression of steroid-converting enzyme genes was quantified. Steroid sulfatase activity was higher in postmenopausal than in premenopausal women both in subcutaneous and in visceral adipose tissue. Visceral fat showed a higher sulfatase activity compared to subcutaneous fat. Three genes in the estradiol-producing pathway, aromatase, 17β-hydroxysteroid dehydrogenase type 12, and hormone-sensitive lipase, were more expressed in postmenopausal than in premenopausal adipose tissue. In conclusion, DHEA fatty acyl esters enhanced the vasodilatory effect of HDL, suggesting that DHEA esters, associated with HDL as cargos, may improve the antiatherogenic function of HDL and thus promote cardiovascular health. Endothelial cells were able to internalize and hydrolyze HDL-associated DHEA fatty acyl esters. The hydrolysis was slow and thus presumably not responsible for the rapid vasodilatory effect of DHEA ester-enriched HDL. Steroid sulfatase activity in adipose tissue was higher in postmenopausal compared to premenopausal women, suggesting that circulating DHEAS could be more efficiently hydrolyzed and utilized in postmenopausal adipose tissue for the formation of biologically active androgens and estrogens. Depot-differences in the sulfatase activity and the gene expression of steroid-converting enzymes suggest that steroid hormone metabolism may differ between subcutaneous and visceral adipose tissue.
  • Korpela, Katri (Helsingin yliopisto, 2016)
    This thesis characterises the development of the intestinal microbiota in healthy children. The influence of four common factors potentially modulating the microbiota prenatal stress, breastfeeding duration, antibiotic use, and probiotic use were investigated, as well as the association between early-life microbiota composition and the development of BMI. In addition, the microbiota in healthy children was contrasted with that that of children with inflammatory bowel disease, characterising the association between treatment response and microbiota. The bacterial composition was analysed from faecal samples using two DNA-based methods, a phylogenetic microarray, as well as sequencing of the 16S rRNA gene amplicons. In addition, real-time qPCR was conducted to measure bile-salt hydrolase genes and antibiotic resistance genes. Bacteria were cultured anaerobically for antibiotic susceptibility testing. The results showed that the microbiota in childhood are sensitive to modulating factors, and are predictive of later-life health. Maternal stress during pregnancy was associated with altered microbiota development over the first months of life. Long duration of breastfeeding was associated with slow microbiota maturation, normal BMI, and low antibiotic use in preschool age, if the microbiota were not disrupted by antibiotic use before weaning. The results indicate that some of the benefits of breastfeeding are microbiota-dependent. Early microbiota maturation was associated with fast growth in infancy and increased BMI in preschool age. Antibiotic use emerged as a central regulator of the microbiome, with potential effects on the metabolic development of the child. Lactobacillus rhamnosus GG supplementation prevented some of the penicillin-associated changes, but failed to prevent the macrolide-associated loss of bifidobacteria. The probiotic supplementation also reduced antibiotic use for at least 3 years after the intervention. In IBD patients, the microbiota composition varied along a gradient of intestinal inflammation and resembled the microbiota composition of antibiotic-treated healthy children. High microbiota similarity to non-antibiotic treated healthy controls predicted positive response to anti-TNF-α treatment in IBD patients. This work suggests that maternal wellbeing is the first step towards healthy microbiota in the child. Promoting a natural microbiota development in childhood by breastfeeding, avoiding unnecessary antibiotics, careful selection of the antibiotic when it is needed, and possibly the use of specific probiotic strains, may have long-term health benefits, particularly in terms of weight development and immune health.
  • Immonen, Tuuli (Helsingin yliopisto, 2016)
    Long-chain acyl-CoA dehydrogenase deficiency (LCHADD), a severe long-chain β-oxidation disorder which, without treatment, usually leads to death, is the most frequent β-oxidation disorder in Finland. Its typical manifestations are hypoketotic hypoglycemia, hepatopathy, failure to thrive, cardiomyopathy, and metabolic crisis during the first year of life. The long term complications are retinopathy and polyneuropathy. In recent years, diagnostics and treatment of LCHADD have produced major advantages. Many countries have implemented LCHADD in their newborn screening programs. Treatment with a low-fat, high-carbohydrate diet with avoidance of fasting is effective. Few follow-up studies, ones on the outcome of LCHADD and whether the current dietary treatment prevents the long-term complications retinopathy and peripheral neuropathy, exist. The aims of the study were to evaluate the clinical course and outcome of LCHADD patients in Finland who have the homozygous c.1528G>C (E510Q) mutation, with strict dietary treatment and develop further their treatment and follow-up strategies. A total of 47 patients with LCHADD caused by a homozygous c.1528G>C mutation were diagnosed in Finland from 1976 through 2014. In our study, the outcome and course of the disease of the LCHADD patients born between 1997 and 2010 (Study II), were compared with an earlier Finnish study of LCHADD patients born 1976 to 1996. In 1976-1996 (N=28) the ten-year survival rate was 14.3%, while in 1997-2010 (N=16) at the end of the study 62.5% were alive. Patients born between 1997 and 2010 presented at the age of 0 to 5 months with hypoketotic hypoglycemia, failure to thrive, hypotonia, hepatomegaly, metabolic acidosis, and cardiomyopathy. The therapy was started 0 to 30 days after diagnosis. Gastrostoma prove beneficial during infancy, ensuring continuous night-time feeding. Most long term survivors were in good overall condition. All except one, who had metabolic crises leading to resuscitation before diagnosis, had a normal intelligence quotient (IQ). We studied the development of polyneuropathy (PNP) by clinical neurophysiologi-cal methods in the LCHADD patients diagnosed between 1965 and 2014 (Study III). Electroneurography (ENG) was performed 1 to 12 times for 12 patients. The first abnormality was reduction in the sensory amplitudes of the sural nerves. During follow-up, progression extended to the upper limbs. Despite good compliance with the diet, of the 10 younger patients, 6 developed polyneuropathy but in a milder form than reported earlier. Their polyneuropathy had been detected at the ages of 6-12 years. To improve the ophthalmological follow-up, we rated the fundus images from seven children in stage 2 retinopathy to create a grading system to monitor retinopathy development (Study I). According to this rating the original staging was divided into three substages of pigmentary deposits (P1-P3) and retinal pigment epithelial (RPE) atrophy (A1-A3). Three ophthalmologists expressed moderate agreement in the assessment of pigmentary deposits (combined weighted K statistic, 0.38), whereas the assessment of RPE atrophy showed poor agreement (combined K statistic 0.018). The visual assessment of fundus photographs based on reference images showed agreement identical to that reported for grading of retinopathy of prematurity, so fundus photography is the suggestion for ophthalmological follow-up of LCHADD retinopathy. We followed up 11 LCHADD patients treated with the current dietary regimen in Helsinki University Central Hospital between 2000-2014 during routine visits (Study IV). Their intake of essential fatty acids (EFAs) was within normal limits. The amount of long-chain triglyceride (LCT) was 5 to 9 percent of total energy intake (E%), consistent with dietary recommendations of LCHADD. We detected, surprisingly, that the patients received one third of their linoleic acid (LA) and α-linolenic (ALA) from their diet and two-thirds from the supplements. Acylcarnitine levels remain elevated, despite good compliance with the diet, which indicated that the diet was not optimal. This demonstrates that in order to keep LCTs as low as possible, we should monitor EFA intake carefully by dietary regimen and by measuring fatty acid profiles. To conclude, the outcome of LCHADD has improved, but the patients still need careful monitoring for dietary compliance in order to prevent retinopathy and neuropathy and especially during infections to prevent hypoglycemia and metabolic decompensation. Future challenges are to adjust the therapy to be lifelong and to find new treatment strategies.
  • Sääksjärvi, Katri (Helsingin yliopisto, 2016)
    Parkinson s disease (PD) is a movement disorder with progressive neurodegeneration. As populations continue to age, the burden of this disease will increase. Although both environmental and genetic factors seem to play a major role in the etiology of PD, the causes of the neuronal death underlying the disease remains largely unknown. As curative treatment for PD remains a challenge, knowledge to aid in the development of prevention tools is crucial. Thus, identifying risk factors, especially modifiable ones, is essential. The aim of the present study was to examine the prediction of dietary, lifestyle and metabolic factors on PD risk in a cohort study design. This study included men and women free from PD at baseline of the Finnish Mobile Clinic Health Examination Survey (FMC, 1966 1972, n=4,524), the Follow-up study of the FMC (FMCF, 1973 1975, n=6,715), and the Mini-Finland Health Survey (1978 1980, n=4,828). Over a follow-up of 22 41 years, the PD cases (International Classification of Diseases 10, code G20, from the World Health Organization) in the FMC (n=85), the FMCF (n=101), and the Mini-Finland Health Survey (n=89) were identified through linkage with the nationwide Drug Reimbursement Register of Social Insurance Institution. Information on lifestyle factors, socioeconomic background, and physiological and biochemical determinants were collected by questionnaires, interview, and health examinations at the baselines of these three surveys. Dietary intake was assessed with a 1-year dietary history interview in the FMC. The exposure factors studied here were diet (individual food groups and items, as well as a diet quality index), leisure-time physical activity, smoking, alcohol consumption, coffee consumption, body mass index, blood pressure, as well as concentration of serum HDL cholesterol, serum triglyceride, fasting plasma glucose, and serum total cholesterol. Cox s proportional hazards model was used to estimate the strength of association between the exposure factors and PD risk. Potential confounding factors were adjusted by inclusion in multivariate models. Most of the individual food groups and items, as well as the diet quality, did not predict the risk of PD. There were few exceptions however, e.g. high consumption of milk was associated with increased PD risk in women. Smoking, heavy consumption of coffee, as well as heavy leisure-time physical activities were associated with decreased PD risk. Alcohol consumption had no clear association with PD risk. Those who had metabolic syndrome had a reduced risk of PD, mainly due to high serum triglyceride and fasting plasma glucose concentration. Serum HDL cholesterol, serum total cholesterol concentration, and blood pressure, however, had no association with PD risk. After taking into account the potential preclinical disease phase, we observed that obesity might increase the risk of PD. In conclusion, diet and other lifestyle factors, as well as metabolic health, may predict the risk of PD. The prospective design of this study is a strength when providing etiologic clues for unraveling the mystery of PD. The overall evidence from the literature is, however, currently too sparse for making recommendations for public health purposes to prevent PD. In the future, perhaps, the results of the present study, as well as previous studies, may be used in clinical practice when planning tools for the early identification of PD patients. Keywords: Parkinson s disease, cohort study, diet, lifestyle factors, metabolic health
  • Tähtinen, Siri (Helsingin yliopisto, 2016)
    According to latest estimates, cancer is becoming an increasing health risk on a global scale. Consequently, novel cancer treatment modalities are urgently needed, especially for the treatment of metastatic solid tumors that are refractory to standard therapies. One promising approach in the treatment of such advanced cancers is immunotherapy which aims to elicit de novo immune responses and/or to boost pre-existing anti-tumor immunity. Different forms of cancer immunotherapy include oncolytic viruses, which selectively replicate in and destroy cancer cells, and adoptive T-cell therapy, in which the patient is given vastly amplified numbers of tumor-targeting T-cells. Both of these have shown capacity to elicit anti-tumor immunity but efficacy in clinical settings has been suboptimal due to different resistance mechanisms employed by solid tumors. Anti-viral resistance represents a major hurdle in oncolytic virotherapy, as repeated administration of the same virus can lead to induction anti-viral rather than anti-tumor immunity. Moreover, cancer cells in some tumors may intrinsically be resistant to virus infection. In study I, we examined whether this could be circumvented by heterologous prime-boost setting, i.e. by switching between oncolytic adenovirus (Ad) and vaccinia virus (VV) during therapy. The results showed that presence of one virus does not preclude the infection of another and treatment with heterologous Ad-VV therapy can delay the onset of anti-viral resistance. Moreover, we found that restricted replication of the priming (adeno)virus can affect the efficacy of heterologous virotherapy. In study IV, we studied the role of anti-viral signaling in adenovirus replication in cancer cells and whether this could be augmented with Janus Kinase 1/2 inhibitor Ruxolitinib. Interestingly, we found that although exposure to type I interferon does not inhibit progressive Ad replication in vitro, significant improvement in anti-tumor efficacy of the virus was observed in vivo when combined to concomitant Ruxolitinib treatment. These results underline the possible approaches that could be taken to reduce naturally acquired or therapy-induced resistance, which interferes with viral spread and may hinder the therapeutic efficacy. Adoptive T-cell therapy (ACT) can be a potent form of immunotherapy. Despite the large number of anti-tumor T-cells infused during ACT, immunosuppression and immune evasion of advanced tumors can render tumor-infiltrating lymphocytes (TILs) inactive. In study II, we examined whether oncolytic adenovirus could increase anti-tumor efficacy of adoptively transferred T-cell receptor (TCR) transgenic T-cells. Indeed, intratumoral injections of adenovirus were able to counteract immunosuppression by activating antigen-presenting cells (APCs) and anti-tumor T-cells. Moreover, an endogenous T-cell response against other, non-related tumor antigens was detected and this polyclonal response contributed to systemic anti-tumor immunity. In study III, we analyzed whether cellular composition of tumor microenvironment could be modified by local administration of immunostimulatory recombinant cytokines. When combined to adoptive T-cell transfer, intratumoral injections of interleukin 2 (IL-2), interferon α (IFN-α) and interferon γ (IFN-γ) resulted in significant anti-tumor efficacy, increased tumor-levels of stimulatory immune cells and reduced exhaustion of CD8+ TILs. In contrast, administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced tumor growth and recruited immunosuppressive cell types such as monocytic myeloid-derived suppressor cells (MDSCs) and M2 macrophages to the tumor bed. These results indicate that immunomodulation by carefully selected cytokines and/or oncolytic adenovirus can sensitize the tumor in favor of adoptively transferred anti-tumor T-cells. In conclusion, different combinatorial approaches can be employed to overcome intrinsic, naturally acquired or therapy-induced resistance to anti-tumor T-cells or oncolytic adenovirus. These advances enable significant improvement in the treatment of solid cancers and can potentially lead to development of curative cancer immunotherapies.
  • Haapamäki, Carola (Helsingin yliopisto, 2016)
    Extrahepatic biliary strictures are mainly managed using stents when treated endoscopically. At present, the main stent types in clinical practice are non expandable plastic stents (NEPS) and self-expandable metallic stents (SEMS), with an up to tenfold cost for the latter. In current praxis, SEMS are widely used for palliative management of malignant biliary strictures as they have longer patency.The role of SEMS in preoperative stenting and the management of benign biliary strictures (BBS) are unclear. The main purpose of this study was to describe the therapy outcome of metallic stenting in anastomotic strictures of liver transplanted (LT) patients, to compare stenting with NEPS and SEMS preoperatively preceding pancreaticoduodenectomy and in BBS caused by chronic pancreatitis (CP) and, finally, to describe stenting of BBS using covered SEMS (cSEMS), a new technique that has not previously been possible, particularly in patients with surgically altered anatomy. The therapy outcome of 17 LT patients with anastomotic biliary stricture or leakage treated with cSEMS was retrospectively analyzed in the piloting study (I). In Study II, the stent success and the surgical outcome of 191 patients preoperatively stented, with either NEPS or SEMS who had undergone pancreatic oduodenectomy or total pancreatectomy were analyzed in a retrospective manner. As a supplementary group, 166 preoperatively unstented and 9 percutaneously, transhepatically drained patients were evaluated concerning surgical outcome. A prospective, randomized, controlled trial was conducted in Study III to compare multiple NEPS with cSEMS therapy in biliary strictures caused by CP, with 30 patients in each group. Study IV presented three patient cases along with detailed description of equipment, devices, technique and outcome, when using cSEMS for BBS in patients with altered anatomy. The median stenting time for the LT patients (I) was 6.8 months (0.9–10.1). The overall stent migration rate was 24%; 100% for Wallstent™ (n=3), 4% for Allium™ (n=13) and 0% for a custom-made Micro-Tech (n=2) stent. There were two recurrences, but eventual stricture resolution was achieved in all patients after restenting. The median follow-up was 21.7 months (6.6–32.0) after stent removal. For the preoperatively stented patients (II), the stent failure rate was 7.4% (95% confidence interval [CI] 4.0%–12.3%) for NEPS and 3.4% (95% CI 0.1%–17.7%) for SEMS, (p=0.697). Among the NEPS stented patients, 45% with a pre-stent bilirubin level exceeding 50 μmol/l reached a preoperative level of 20 μmol/l or less, compared with 26% in the SEMS group (p=0.110). A level lower than 50 μmol/l was achieved by 80% of patients in the NEPS group and by 61% in the SEMS group (p=0.058). The bile juice bacterial scores did not differ between the differently stented patients but a statistically significant difference was found when the proportion of sterile bile juices in unstented patients with biliary obstruction (100%; n= 7/7) was compared with that of the stented patients (1%; n=1/155; p<0.001). Postoperative infection complications did not show any significant difference when comparing these stented and unstented groups with biliary obstruction. However, the number of unscented patients with biliary obstruction was very small. Overall postoperative infections, postoperative pancreatic fistulas or reoperations showed no significant difference between study groups. For the patients with CP and BBS (III), the median follow-up was 40 months (range 1–66 months). The stricture-free success rate at two years was 90% (95% CI 72%–97%) in the NEPS group and 92% (95%CI 70%–98%) in the cSEMS group (p=0.405). One late recurrence in the NEPS group, 50 months after stent removal, decreased the success rate to 72% (95% CI 27%–92%). The migration rate was 10%in the NEPS group and 7% in the cSEMS group (p=1.000). Three patients with altered anatomy and BBS successfully received an endoscopically deployed cSEMS, two of them utilizing the rendezvous technique, as the percutaneous transhepatic cholangiogram (PTC) route was available when the procedure was started (IV). In conclusion, endoscopic therapy with cSEMS is safe and efficient both regarding anastomotic complications after LT and CP-induced BBS. Progressive stenting with NEPS is a good alternative in BBS caused by CP, however, with impaired patient comfort. In ordinary preoperative stenting, SEMS do not seem to offer any advantage over NEPS. In patients with altered anatomy, endoscopic deployment of cSEMS in BBS has become possible, as equipment and devices have evolved.
  • Andrade Barazarte, Hugo (Helsingin yliopisto, 2016)
    Objective Multiple intracranial aneurysms are frequent, with an incidence of 15-40% among intracranial aneurysms carriers. Of these carriers, 20-40% have bilateral intracranial aneurysms. The rupture risk is higher for patients with multiple intracranial aneurysms. For those patients, several treatment options are available (microsurgery comprising a unilateral-contralateral approach, bilateral craniotomies in one-stage or two stages surgery, and endovascular methods) varying from institution s resources and surgeon s experience. The present study focuses and analyses the angiographic characteristics, specific parameters, and surgical results of the unilateral-contralateral approach for ICA-opht segment and MCA aneurysms. In addition, it describes and analyses the proximal vascular control by transient cardiac arrest induced by adenosine during the contralateral clipping of ICA-opht segment aneurysms. Patients and Methods We retrospectively reviewed 68 patients with ICA-opht segment and bMCA aneurysms treated through a contralateral approach at the department of neurosurgery of the University of Helsinki, between January 1998 and December 2013. A detailed analyses of the aneurysms characteristics and constrains of the contralateral surgical corridor was performed. A further subgroup analysis of 8 patients harboring ICA-opht segment aneurysms approached through a contralateral craniotomy and requiring intravenous adenosine administration to induce transient cardiac arrest during microsurgical clipping was performed as well. Results ICA-opht segment aneurysms: All the 30 ICA-opth aneurysms were small (less than 7 mm), unruptured, saccular, and had no wall irregularities, calcifications or secondary pouches. Microsurgical clipping of these aneurysms was possible when the prechiasmatic distance had a median of 5.7 mm (range 3.4-8.7 mm) and the interoptic distance a median of 10.5 mm (range, 7.6-15.9). The most frequent aneurysm dome projection was superomedial (77%). Of the patients with ICA-opht segment aneurysms approached through a contralateral craniotomy, 93% had good postoperative outcome at 3-month follow-up. bMCA aneurysms: The contralateral approach for bMCA aneurysms was possible in 38 patients. All the 38 contralaterally approached MCA aneurysms were unruptured and had saccular shape (expect one with bilobular shape). The majority (97%) of contralateral aneurysms were small to medium in size. The median length of the contralateral A1 was 13.2 mm (range: 6-19.8 mm), and the median length of the contralateral M1 was 14.2 mm (range: 4.6-21 mm). Of the patients with unruptured bMCA aneurysms treated through a contralateral approach, 24 (86%) patients had good outcome and 4 (14%) had poor outcome at 3-month follow-up, 1 patient was lost to follow-up. There were 9 patients harboring bMCA aneurysm presented with SAH due to a ruptured ipsilateral aneurysm. Of these patients, 7 (78%) had good outcomes, and 2 (22%) had poor outcomes at 3 months. Olfactory disturbances were present in 21% of cases treated through a contralateral approach. Transient cardiac arrest induced by adenosine during contralateral clipping of ICA-opht aneurysms: 8 patients received intravenous bolus of adenosine to induce transient cardiac arrest during clipping. Of the total patients, 5 received single bolus of adenosine, and 3 patients received multiple doses. The median single dose of adenosine was 22.5 mg (range, 5-50 mg). The asystole time range between 20-40 seconds after adenosine administration. All the 8 patients showed good surgical outcomes at 3-month and 1-year follow-up, and showed no procedure-related complications. Conclusion: The contralateral approach remains as a feasible option for microsurgical treatment of ICA-opht segment aneurysms, and bMCA aneurysms. Its feasibility depends on general parameters related to the aneurysm itself (shape, morphology, size, status and projection), and specific parameters that varies according to the vascular segment to be treated (prechiasmatic and interoptic distances, length of A1 and M1). Transient cardiac arrest induced adenosine represents a useful tool to obtain proximal vascular control while performing a contralateral approach for ICA-opth segment aneurysms in selected patients.
  • Göhre, Felix (Helsingin yliopisto, 2016)
    Objective: Aneurysms of the posterior cerebral artery are rare vascular lesions. The overall incidence is less than 1%, representing around 7% of posterior circulation aneurysms. Due to this low incidence, most of the institutional series on PCA aneurysms are small and contain less than 25 patients. Only one other series comparable in scope to ours has been previously published. The presented study analyzes and describes the characteristic features of PCA aneurysms as well as investigates the relevant treatment strategies and their outcomes. A particular focus is in the description and analysis of PCA aneurysms treated from a subtemporal approach and the pres - entation of an associated aneurysm treatment from a lateral supraorbital approach. Patients and Methods: We reviewed 121 patients diagnosed with 135 PCA aneurysms, all of whom were treated between 1980 and 2012 at two Finnish neurosurgical units (Department of Neurosurgery at the University of Eastern Finland, Kuopio and Department of Neurosurgery at the University of Helsinki). Additionally, twelve historical (pre-1980) cases were presented. Detailed analyses of cerebral angiographies were conducted for 93 PCA aneurysms in 81 patients. A further subgroup analysis of 34 patients diagnosed with 37 PCA aneurysms treated via subtemporal approach was also performed. Results: Of the 121 patients with 135 PCA aneurysms, 52 (39%) aneurysms were ruptured and 83 (61%) unruptured . The following distribution along the PCA segments was observed: P1 segment (n=53), P1/2 junction (n=39), P2 segment (n=28), and P3 segment (n=15); no P4 segment aneurysms were found. Saccular aneurysms were more common than fusiform PCA aneurysms (76% vs. 24%). The detailed angiographic analysis showed that the median aneurysm size was 7 mm for ruptured PCA aneurysms and 4 mm for unruptured aneurysms. Saccular aneurysms (n=69, 74%) had a characteristic dome projection for each location: P1 segment, upward (67%); P1/P2 junction, anterior/upward (80%); P2 segment, lateral (67%); and P3 segment, posterior (50%). The following treatment results at 1-year follow-up were achieved for patients with: unruptured PCA aneurysms (n=19; 12 good outcomes, 63%; 6 moderate, 31%; 1 poor, 5%), ruptured PCA aneurysms (n=27; 10 good, 37%; 9 moderate, 33%; 8 poor, 30%), and patients with complex neurovascular pathologies and PCA aneurysms (n=96; 42 good, 43%; 40 moderate, 42%; 14 poor, 15%). Analyzing the subtemporal approach we found that most complications were not related to the subtemporal approach itself but to the specific nature of the PCA aneurysms treated and the chosen strategy. The most common (12 out of 34; 35%) serious complication in this series was an ipsilateral PCA infarction after parent vessel occlusion. Conclusion: PCA aneurysms are infrequent vascular lesions that are often associated with other vascular pathologies. Most ruptured PCA aneurysms are smaller than 10 mm and distally located. The saccular PCA aneurysms have a typical dome orientation at each PCA segment. Microsurgery and endovascular treatment are effective options for the occlusion of PCA aneurysms. As a result, individual treatment strategies are required. Despite commonly adequate vessel collateralization of the distal PCA territory, preservation or reconstruction of the parent vessel is crucial for favorable treatment outcomes. The subtemporal approach is favorable for the treatment of PCA aneurysms in proximity to the tentorium. Frontolateral approaches allow the treatment of proximal PCA aneurysms and ipsilateral anterior circulation aneurysms inside the Circle of Willis.
  • Laulajainen-Hongisto, Anu (Helsingin yliopisto, 2016)
    Acute otitis media (AOM) is an infection that is particularly common in children. The bacterial etiology of AOM, in both children and adults, affects its clinical picture. While in some cases the infection can simply be carefully monitored without treatment, antimicrobials are often prescribed. Caution is required, however, when prescribing antimicrobials as their excessive use has led to antimicrobial resistance; this resistance has been seen among some of the causative pathogens for these infections. Before the development of antimicrobial treatment, complications due to middle ear infections were common, potentially causing severe symptoms or even death. Some middle ear infections spread into surrounding structures, leading to intratemporal or extratemporal (extracranial or intracranial) complications. This thesis focuses on complicated otitis media and the causative factors of its complications. In the first two studies, we evaluated the medical records of all (n=100) children (0-16 years old) hospitalized at the Department of Otorhinolaryngology in the Helsinki University Hospital from 2003 to 2012 for acute mastoiditis (AM) or AOM, as well as the infection s bacteriology in relation to the patient s clinical findings and treatment. Using this information, we analyzed the differences in the etiologies and clinical pictures of those children hospitalized due to AOM compared to AM. In our third study, we examined the medical records of all (n=166) patients hospitalized at our institution from 1970 to 2012 due to intracranial abscesses (IA), including those of otogenic background (oIA). In the fourth study, we evaluated the bacteriology in relation to the patients clinical findings and treatment in all (n=160) adult patients treated at our institution from 2003 to 2012 for AOM or acute mastoid infection. In adults, acute mastoid infection was subclassified into AM, latent mastoiditis (LM), and AM following chronic middle ear infection (AMc). The clinical picture of AM in children differed according to the causative pathogen. Streptococcus pneumoniae (Pnc), especially its resistant strains, caused severe symptoms and often led to mastoidectomies. Pseudomonas aeruginosa (Ps) typically affected older children with prior tympanostomy tubes and generally caused milder symptoms. Furthermore, the bacteriological etiology of hospitalized AOM and AM patients was different compared to outpatient AOM. Two of the typical AOM pathogens, Haemophilus influenzae (Hi) and Moraxella catarrhalis (Mc), were uncommon among the hospitalized patients. Pnc, especially its resistant strains, was less common in children hospitalized for AOM compared to AM, and less common in adults than children. Streptococcus pyogenes (StrA) and Ps were both linked to otorrhea and were found only in older children. Over our 42 year study period, oIAs became less common and typically developed following chronic middle ear infections, often in connection with cholesteatoma. In adults, the bacteriological etiology and clinical picture of AMc differed from AOM as well as the other acute mastoid infection types (AM, LM). AOM and AM led to less surgical procedures than the more prolonged forms of acute mastoid infection (LM, AMc). In children, the hospitalized cases of AOM and AM differed from outpatient AOM. In adults, severe AOM, AM, and LM seem to compose a continuum that may lead to chronic otitis media and its acute complications, including oIAs. Otogenic IAs are quite rare, however, and became less common over our study period.
  • Markkula, Niina (Helsingin yliopisto, 2016)
    Depressive disorders are a major public health concern worldwide due to their pervasiveness, often chronic or recurrent course and serious adverse outcomes. These include psychosocial disability, reduced quality of life, physical health problems and increased mortality. This study examined prevalence, predictors and different adverse outcomes of depressive disorders (major depressive disorder and dysthymia) in a general population setting. Specifically, the study aimed to establish the prevalence of depressive disorders in Finland in 2011 and assess possible changes over the past decade; to examine risk factors for new-onset depressive disorders; to investigate the long-term prognosis of depressive disorders and its determinants; and to assess excess mortality associated with depressive, anxiety and alcohol use disorders. A large longitudinal study of the Finnish population, consisting of the Health 2000 and Health 2011 Surveys, was used to investigate these questions. The survey data was complemented with data from the Care Register for Health Care and the Finnish Causes of Death Statistics. The results show that one in 10 adults in Finland suffered from a depressive disorder in 2011, and the prevalence increased from 2000 to 2011, particularly among women. Methods to account for non-participation also showed that the non-participation of people with depressive disorders in population studies significantly biases prevalence estimates. People who were younger, had a history of multiple childhood adversities, lower trust axis of social capital, or an anxiety disorder or subclinical depressive symptoms at baseline, had a higher risk of developing depressive disorders. In addition, having three or more physical diseases was a risk factor for dysthymia. Among people with depressive disorders at baseline, 34-43% still had some depressive, anxiety or alcohol use disorder after 11 years, and 48-61% had clinically significant depressive symptoms. Unmarried people and those with more severe initial symptoms had a higher risk of persistent course. People with depressive disorders had a twofold mortality risk, whereas the risk was 1.7-fold in alcohol use disorders and was not increased in anxiety disorders, when adjusted for other risk factors. This study confirms that depression is an increasing public health concern in Finland, and that depressive disorders have serious long-term consequences. To reduce the burden of depressive disorders, it is of key importance to develop primary prevention efforts and measures to reduce the negative health and social consequences of depression.
  • Backlund, Michael (Helsingin yliopisto, 2016)
    The renin-angiotensin system is a key regulator of blood pressure and electrolyte homeostasis. Most hemodynamic responses to angiotensin II are mediated via angiotensin II type 1 receptor (AT1R). The 3 -untranslated region (3 UTR) of AT1R mRNA is important in posttranscriptional regulation of AT1R expression. It contains multiple adenylate-uridylate-rich elements that are recognized by various RNA-binding proteins (RNBP) affecting the stability, conformation, subcellular localization, and translation of their target mRNAs. The aim of this study was to identify novel AT1R 3 UTR-binding RNBPs and understand their physiological role in AT1R function. AT1R 3 UTR-associated RNBPs were isolated from human vascular smooth muscle cells by protein affinity purification using AT1R 3 UTR as a probe. Mass spectrometric identification of the isolated proteins led to identification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), Hu antigen R (HuR) and TIA1 cytotoxic granule-associated RNA-binding protein (TIA-1). GAPDH was identified as a novel AT1R mRNA-binding protein that suppresses AT1R translation. GAPDH binds to a hairpin-structure rich in adenosine and uridine in the proximal region of AT1R 3 UTR. Hydrogen peroxide-induced oxidative stress increased AT1R expression by dissociating GAPDH from AT1R 3 UTR and relieving it from the GAPDH-mediated suppression. Insulin-induced increase in AT1R expression was shown to be posttranscriptionally mediated by HuR. Insulin stabilized AT1R mRNA in a 3 UTR-dependent manner and HuR was shown to bind AT1R 3 UTR. Insulin induced nucleocytoplasmic translocation of HuR to cytoplasm and increased HuR binding to AT1R 3 UTR. This increased AT1R expression via stabilization of AT1R mRNA. AT1R avoids the endoplasmic reticulum (ER) stress-mediated translational suppression. Binding of TIA-1 to AT1R 3 UTR was shown to suppress AT1R expression. TIA-1 normally colocalized with AT1R mRNA in the cytoplasm. However, during ER stress TIA-1 was dissociated and directed to translationally silenced stress granules, while AT1R mRNA remained excluded from them. Thus, AT1R mRNA avoids aggregation to SGs and TIA-1-mediated translational suppression during ER stress. In conclusion, oxidative stress, insulin, and ER stress regulates AT1R expression posttranscriptionally by affecting the binding of GAPDH, HuR, and TIA-1 to its mRNA 3 UTR.
  • Lassenius, Mariann (Helsingin yliopisto, 2016)
    Around one-third of patients with type 1 diabetes develop diabetic nephropathy. Even though the pathogenesis of diabetic nephropathy is not fully understood, the process involves several environmental factors. Low grade inflammation has been linked to many metabolic diseases and is also evident in patients with type 1 diabetes, especially in the presence of nephropathy. Bacterial lipopolysaccharides (LPS) are powerful triggers of inflammation, but whether low grade inflammation is caused by these components is an open question. The aim of this thesis was to examine the relationship between LPS and the development of diabetic nephropathy, inflammation, vascular function, lipid metabolism, and intestinal homeostasis in patients with type 1 diabetes. The studies are part of the ongoing Finnish Diabetic Nephropathy Study (FinnDiane), a nationwide, multicenter study that aims to identify genetic and environmental risk factors for the development of diabetic complications in patients with type 1 diabetes. Study I was a follow-up study, and Studies II IV were cross-sectional in their design. Renal status was verified at follow-up by laboratory data and a review of all available medical files (Study I). Study II included, in addition to patients with type 1 diabetes, patients with IgA glomerulonephritis and non-diabetic control subjects. The participants in Studies III and IV had three consecutive high-fat meals and were followed for 10 hours postprandially. Factors associated with endotoxemia, vascular function, inflammation, and lipid metabolism were investigated. For all studies, LPS was measured by the limulus amebocyte lysate (LAL) assay from serum samples. In the patients with type 1 diabetes, high serum LPS activity at baseline was associated with the development of microalbuminuria during the follow-up. High serum LPS was also associated with features of the metabolic syndrome in both the patients with type 1 diabetes and the overweight non-diabetic controls. Of note, no accumulation of LPS in the circulation was evident in response to three high-fat meals. However, the patients with type 1 diabetes showed altered postprandial lipid metabolism and vascular response. Moreover, factors associated with gut homeostasis were altered in the patients with type 1 diabetes compared to the non-diabetic controls. We show that high serum LPS is associated with the development of diabetic nephropathy and features of the metabolic syndrome. The metabolic syndrome is associated with insulin resistance, and it is a risk factor for both diabetic nephropathy and cardiovascular disease. Endotoxins may affect the development of diabetic nephropathy through the direct disruption of the filtration barrier, but also through insulin resistance at both the tissue and systemic levels. In response to acute high-fat feeding, no evidence for LPS accumulation was seen. However, unfavorable changes in lipid metabolism and vascular response in patients with type 1 diabetes may render them at higher cardio-metabolic risk. This risk may be further enhanced by adverse changes in both inflammatory and protective factors in the gut, leading to a possibly higher gut permeability and an increase in circulating endotoxins.
  • Yukin, Alexey (Helsingin yliopisto, 2016)
    This Thesis addresses fundamental mechanisms of brain disorders that occur in preterm infants or during early childhood. To this end, we have developed animal models to mimic disorder-specific pathological conditions in the brain. During critical periods of development of the mammalian brain, cell migration and synapse formation are crucially important to set up newly developed neuronal circuits that will support complex network activity. A particular set of cells, the subplate neurons, is the first to mature during the earliest stages of cortical development. These neurons act as transient relay and processing station for signals coming from subcortical structures to the cortex. Their high dependence on oxygen supply makes them vulnerable to injuries that take place during pregnancy. In the present work, conditions of this kind were mimicked by specific toxin-based ablation of subplate neurons. At a more advanced stage of brain development, a very common type of brain disorder is febrile seizures (FS). They represent convulsive events in humans that are promoted by respiratory alkalosis during febrile illness. The global incidence of FS is estimated from 2 to 14 % (depending on ethnicity) of all children in the age of 6 months to 5 years. Using an animal based on 13-14 day old rats exposed to hyperthermia, we show that a pro-excitatory action of GABA based on the neuron-specific carbonic anhydrase (CA) isoform VII is crucially involved in the generation of these seizures. Finally, while it is widely assumed that FS are limbic in origin, this Thesis provides new evidence that the brainstem can have an independent and prominent role in the generation of FS, and also of convulsions induced by kainic acid, which so far, have been considered prototypical in studies of limbic seizures. As a whole, this work demonstrates the high utility and heuristic value of custom-designed animal models in studies of basic mechanisms and consequences of disorders in the developing brain.
  • Rozov, Stanislav (Helsingin yliopisto, 2016)
    The histaminergic neurons of the hypothalamus in conjunction with hypocretinergic cells, monoaminergic nuclei of the brainstem and basal forebrain centers, constitute the ascending arousal system that plays a pivotal role in maintenance of wakefulness state. It has predominantly inhibitory reciprocal connections to their sleep-active counterparts, which enables an efficient transition between wakefulness and sleep. In combination with the circadian clock and homeostatic regulation of sleep its forms a network that regulate the sleep-wakefulness cycle. Because of the complex organization, it becomes difficult to estimate the significance of the crosstalk between the individual components of this regulatory network. Therefore, we focused on examination of interactions between the histaminergic system, the circadian and homeostatic components. We used electroencephalography in combination with behavioral analysis to quantify changes in spontaneous locomotion, wakefulness, non-rapid eye movement sleep and rapid eye movement sleep stages in response to an alterations of pacemaker rhythm. The shortening of the light-dark cycle led to re-distribution of these parameters towards aperiodicity, as well as increased sleep propensity, diminished daily rhythms of power of high θ-, and γ-waves, which are characteristic of an active wakefulness state as well as strengthened the phase-amplitude coupling between these frequencies. We used in vivo microdialysis in combination with sleep deprivation to understand the histaminergic regulation of homeostatic sleep propensity. During 6-hours of sleep deprivation, the histamine release was upregulated and comparable to its level during wakefulness, whereas when the sleep deprivation ceased, the release of histamine immediately dropped to the baseline level. To assess the effects of circadian regulation on histaminergic neurons, we estimated the daily changes of activities of the key enzymes involved in the histamine metabolism, histidine decarboxylase and histamine-N-methyltransferase as well as diurnal profile of histamine release. The 24-hour rhythms of production and release of histamine and its metabolite, 1-methylhistamine were detected, whereas activities of the enzymes had no detectable diurnal rhythm. Histamine release was highly positively correlated with changes in the power of the θ-frequency range. In order to understand the possible role of the histaminergic regulation of circadian system functioning we utilized mouse strains that constitutively lack histamine 1 and 3 receptors. The lack of histamine 1 receptor had no effects on the circadian rhythm of spontaneous locomotion, but the knockout of the histamine 3 receptor resulted in a substantial reduction of free-running activity rhythm amplitude. The expressions of the core clock genes, Per1, Per2 and Bmal1, in the suprachiasmatic nuclei of the hypothalamus, the cerebral cortex and the striatum were not affected in these knockout models. Based on the acquired results we concluded that the circadian process may affect homeostatic regulation, thus indicating an interaction of these processes. The circadian regulation of the histaminergic neurons takes place mainly at the level of histamine accumulation and release. In contrast, alterations in histamine-mediated signal transduction caused only minor alterations in examined circadian rhythms. Finally, we could not find evidence of an involvement of the histamine in homeostatic regulation of sleep-wakefulness cycle.
  • Vaahersalo, Jukka (Helsingin yliopisto, 2016)
    Aims The objectives of this study were to evaluate the incidence and neurological outcomes of out-of-hospital cardiac arrest (OHCA) patients in Finnish intensive care units (ICU). This study also investigated the use of therapeutic hypothermia (TH), arterial blood gas (ABG) pressures and different biomarkers association with one-year neurological outcome after OHCA. Materials and methods The FINNRESUSCI study was conducted in 21 out of 22 ICUs in Finland during a one-year study period. All adult patients after OHCA who were treated in ICU were included. Blood samples for biomarker evaluation were collected and neurological outcomes were determined 12 months after CA. All patients were included when evaluated the incidence, the implementation of TH and outcomes. In Study II, all ABG samples obtained from mechanically ventilated patients during the first 24h from ICU admission. In Study III and IV, biomarkers were measured from patients resuscitated from VF/VT. Main results FINNRESUSCI study included 548 patients, of whom 311 (56.8%) had shockable (VF/VT) and 237 (43.2%) non-shockable (PEA or asystole) as an initial rhythm. TH was induced totally in 311 unconscious patients 85.8% in VF/VT and 31.4% in PEA or asystole group. Good neurologic outcome was achieved in 58.0% patients with shockable rhythms and in 19.4% with non-shockable rhythms after TH treatment. The mean PaCO2 tension during the first 24-hour in ICU was an independent predictor of a good outcome with an odds ratio (OR) of 1.054, but the mean PaO2 tension was not. The time spent above PaCO2 45 mmHg was associated with good neurologic outcome and patients with the highest mean PaCO2 and PaO2 values had better neurologic outcome than predicted with an OR of 3.2 (95% CI 1.1-9.2). IL-6 and S-100B was associated with time to ROSC and poor neurological outcome (p less than 0.001). Admission IL-6 was associated with extra-cerebral organ dysfunction (p less than 0.001) and was an independent predictor of poor neurological outcome with an OR of 1.006 (95% CI 1.000-1.011). Hs-TnT levels were elevated in all of the patients, higher in patients with poor vs. good neurological outcome 739 vs. 334 ng/l (p=0.028), but there was no statistical difference in mortality. Conclusions TH is well implemented in clinical practice in Finnish ICUs. The majority of OHCA patients with shockable rhythms survive with good neurology, while the outcome of patients with non-shockable rhythms is poorer despite the TH treatment. There was no harmful association between hyperoxia and outcome, but instead mild hypercapnia combined with mild hyperoxia might be beneficial during the first 24 hours. IL-6 was associated with extra-cerebral organ dysfunction and predicted neurological outcome after OHCA-VF/VT, while hs-TnT does not give any additional prognostic information.