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  • Salmikangas, Paula (Helsingin yliopisto, 2001)
  • Mätzke, Sorjo (Helsingin yliopisto, 2004)
  • Hernandez Rios, Marcela (Helsingin yliopisto, 2012)
    Chronic periodontitis results from a complex aetiology, including the formation of a subgingival biofilm and the elicitation of the host s immune and inflammatory response. The hallmark of chronic periodontitis is alveolar bone loss and soft periodontal tissue destruction. Evidence supports that periodontitis progresses in dynamic states of exacerbation and remission or quiescence. The major clinical approach to identify disease progression is the tolerance method, based on sequential probing. Collagen degradation is one of the key events in periodontal destructive lesions. Matrix metalloproteinase (MMP)-8 and MMP-13 are the primary collagenolytic MMPs that are associated with the severity of periodontal inflammation and disease, either by a direct breakdown of the collagenised matrix or by the processing of non-matrix bioactive substrates. Despite the numerous host mediators that have been proposed as potential biomarkers for chronic periodontitis, they reflect inflammation rather than the loss of periodontal attachment. The aim of the present study was to determine the key molecular MMP-8 and -13 interactions in gingival crevicular fluid (GCF) and gingival tissue from progressive periodontitis lesions and MMP-8 null allele mouse model. In study (I), GCF and gingival biopsies from active and inactive sites of chronic periodontitis patients, which were determined clinically by the tolerance method, and healthy GCF were analysed for MMP-13 and tissue inhibitor of matrix metalloproteinases (TIMP)-1. Chronic periodontitis was characterised by increased MMP-13 levels and the active sites showed a tendency of decreased TIMP-1 levels associated with increments of MMP-13 and total protein concentration compared to inactive sites. In study (II), we investigated whether MMP-13 activity was associated with TIMP-1, bone collagen breakdown through ICTP levels, as well as the activation rate of MMP-9 in destructive lesions. The active sites demonstrated increased GCF ICTP levels as well as lowered TIMP-1 detection along with elevated MMP-13 activity. MMP-9 activation rate was enhanced by MMP-13 in diseased gingival tissue. In study (III), we analysed the potential association between the levels, molecular forms, isoenzyme distribution and degree of activation of MMP-8, MMP-14, MPO and the inhibitor TIMP-1 in GCF from periodontitis progressive patients at baseline and after periodontal therapy. A positive correlation was found for MPO/MMP-8 and their levels associated with progression episodes and treatment response. Because MMP-8 is activated by hypochlorous acid in vitro, our results suggested an interaction between the MPO oxidative pathway and MMP-8 activation in GCF. Finally, in study (IV), on the basis of the previous finding that MMP-8-deficient mice showed impaired neutrophil responses and severe alveolar bone loss, we aimed to characterise the detection patterns of LIX/CXCL5, SDF-1/CXCL12 and RANKL in P. gingivalis-induced experimental periodontitis and in the MMP-8-/- murine model. The detection of neutrophil-chemoattractant LIX/CXCL5 was restricted to the oral-periodontal interface and its levels were reduced in infected MMP-8 null mice vs. wild type mice, whereas the detection of SDF-1/CXCL12 and RANKL in periodontal tissues increased in experimentally-induced periodontitis, irrespectively from the genotype. Accordingly, MMP-8 might regulate LIX/CXCL5 levels by undetermined mechanisms, and SDF-1/CXCL12 and RANKL might promote the development and/or progression of periodontitis.
  • Anttila, Timo Verneri (Helsingin yliopisto, 2010)
    Migraine is the common cause of chronic episodic headache, affecting 12%-15% of the Caucasian population (41 million Europeans and some half a million Finns), and causes considerable loss of quality of life to its sufferers, as well as being linked to increased risk for a wide range of conditions, from depression to stroke. Migraine is the 19th most severe disease in terms of disability-adjusted life years, and 9th among women. It is characterized by attacks of headache accompanied by sensitivity to external stimuli lasting 4-72 hours, and in a third of cases by neurological aura symptoms, such as loss of vision, speech or muscle function. The underlying pathophysiology, including what triggers migraine attacks and why they occur in the first place, is largely unknown. The aim of this study was to identify genetic factors associated with the hereditary susceptibility to migraine, in order to gain a better understanding of migraine mechanisms. In this thesis, we report the results of genetic linkage and association analyses on a Finnish migraine patient collection as well as migraineurs from Australia, Denmark, Germany, Iceland and the Netherlands. Altogether we studied genetic information of nearly 7,000 migraine patients and over 50,000 population-matched controls. We also developed a new migraine analysis method called the trait component analysis, which is based on individual patient responses instead of the clinical diagnosis. Using this method, we detected a number of new genetic loci for migraine, including on chromosome 17p13 (HLOD 4.65) and 10q22-q23 (female-specific HLOD 7.68) with significant evidence of linkage, along with five other loci (2p12, 8q12, 4q28-q31, 18q12-q22, and Xp22) detected with suggestive evidence of linkage. The 10q22-q23 locus was the first genetic finding in migraine to show linkage to the same locus and markers in multiple populations, with consistent detection in six different scans. Traditionally, ion channels have been thought to play a role in migraine susceptibility, but we were able to exclude any significant role for common variants in a candidate gene study of 155 ion transport genes. This was followed up by the first genome-wide association study in migraine, conducted on 2,748 migraine patients and 10,747 matched controls followed by a replication in 3,209 patients and 40,062 controls. In this study, we found interesting results with genome-wide significance, providing targets for future genetic and functional studies. Overall, we found several promising genetic loci for migraine providing a promising base for future studies in migraine.
  • Tikka-Kleemola, Päivi (Helsingin yliopisto, 2009)
    Common migraine, i.e. migraine with (MA) or without aura (MO), is a chronic neurological disorder affecting about 10% of the Caucasian population. In MA, migraine headache is preceded by visual, sensoric and/or dysphasic reversible aura symptoms. Twin and family studies have suggested a multifactorial mode of inheritance for common migraine, and a stronger genetic component for MA than for MO. Since there is no biological or genetic marker to identify common migraine, aura symptoms provide a distinctive character to identify those suspected of suffering from migraine. The aim of this study was to identify MA susceptibility loci in well-phenotyped migraine samples with familial predisposition using different gene mapping methods. Genes coding for endothelin1 and its receptors EDNRA and ENDRB are potential candidate genes for cortical spreading depression (CSD), which is considered to be the underlying mechanism of migraine aura. The role of these genes in MA was studied in 850 Finnish migraine cases and 890 control individuals. Rare homozygous EDNRA SNPs showed nominal association with MA and with the age of onset trait (20 years). This result was also detected in the pooled analysis on 648 German MA cases and 651 control individuals when the test was adjusted for gender and sample origin. Evaluation of SNP genotyping reactions with two different DNA polymerase enzymes ensured that the genotype quality was high, and thus the discovered associations are considered reliable. The role of the 19p13 region was studied in a linkage analysis of 72 Finnish MA families. This region contains two migraine-associated genes: CACNA1A, which is associated with a predisposition to a rare Mendelian form of MA, familial hemiplegic migraine (FHM), and the insulin receptor gene (INSR) that is associated with common migraine. No evidence of linkage between the 19p13 and MA was detected. A novel visual aura locus was mapped to chromosome 9q21-q22 with significant evidence of linkage using a genome-wide linkage approach in 36 Finnish MA families. Five additional, potential loci were also detected. The 9q21-q22 region has previously been linked to occipitotemporal lobe epilepsy and MA, both of which involve prominent visual symptoms. Our result further supports a shared background for these episodic disorders.
  • Hahtola, Sonja (Helsingin yliopisto, 2008)
    Cutaneous T-cell lymphomas (CTCL) represent a group of non-Hodgkin lymphomas showing a growing incidence especially in the Western world. The mechanisms leading to the disease are largely unknown, diagnosis is difficult and therefore often delayed, and no curative therapy exists. CTCL presents with skin symptoms although the malignant cells are not derived of human skin but of human immune system instead. The malignant cells are mature T helper memory cells, and preferentially express cytokines characteristic to T-helper 2 (Th2) type immune response. Chromosomal instability is a typical feature of CTCL. Some secondary cancers occur in CTCL patients more often than in general population, the most common of which are lung cancers and non-Hodgkin lymphomas. The aim of the study was to identify genes relevant to CTCL pathogenesis to clarify the poorly understood pathomechanisms behind the disease group. The two most common subgroups of CTCL, mycosis fungoides (MF) and Sezary syndrome (SS), as well as the difficult to diagnose subcutaneous panniculitis like T-cell lymphoma (SPTL), were studied. To reveal the molecular pathogenesis underlying CTCL-associated lung cancer, CTCL-associated lung cancer samples were analysed and compared to primary / reference lung cancer samples. Identification of potential novel diagnostic markers as well as target molecules for therapy was a special focus of the study. To achieve this, patient derived material was studied with molecular cytogenetic techniques, microarrays and gene expression analyses. This study identified the first specific, recurrent gene-level aberration in CTCL, namely the deletion / translocation of neuron navigator 3 (NAV3) gene, characteristic to many different CTCL subgroups, namely MF, SS, and SPTL. NAV3 is a putative haploinsufficient tumor suppressor influencing the differentiation of T-helper cells. The pathways affected by its aberrant function, are currently being studied. Novel insights to CTCL pathogenesis were achieved through the observation that several genes specific for Th1 type immune response (e.g. T-bet, RANTES, and NKG7) were downregulated in CTCL. For the first time, CTCL-associated lung cancers were observed to show chromosomal aberrations differing from primary lung cancers. This finding warrants further prospective studies to identify the common underlying factors between CTCL and CTCL-associated lung cancer. Demonstration of NAV3 deletion by FISH provides a novel diagnostic tool, and overexpression of certain membrane antigens (e.g. MS4A4A, LIR9 and CD52) will provide the basis for developing novel antibody-based therapeutic means.
  • Aavikko, Mervi (Helsingin yliopisto, 2014)
    Identification of tumor susceptibility genes has contributed significantly to our understanding on molecular basis of cancer. Over one hundred high risk tumor susceptibility genes have been identified during past few decades, but some remain still to be characterized, including those that do not cause other clinically recognizable syndromic features, and present with incomplete penetrance. The aim of this study was to assess the familial aggregation of cancers in Finland and to identify novel tumor predisposition families and genes in families with Kaposi sarcoma (KS), nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), and intracranial meningioma. First, to assess the familial aggregation of cancers in Finland, we conducted a computerized clustering of 878 593 patients in FCR, based on family name at birth, municipality of birth, and tumor type. Additional clustering, based on family name at birth and tumor type, was also conducted. We calculated a cluster score to assess the frequency of familial aggregation of different tumor types. The top scoring types included those with well-established genetic background, but also those with unknown genetic etiology such as KS. We performed genealogy analysis from the clustered KS cases, and identified a family with five affected individuals and several smaller KS families. Furthermore, we showed that KS incidence is unevenly distributed in Finland, with more cases in the western and northeastern than other parts of the country. Second, we examined the genetic susceptibility in the KS family with five affected cases. We mapped the shared genomic regions and performed whole genome and exome sequencing. We identified 14 candidate variants, among them a missense variant (c.1337C>T, p.Thr446Ile) in the DNA binding domain of STAT4. We showed that healthy variant carriers had decreased IFN-γ production in the activated T-cells. We studied STAT4 in a large number of familial and sporadic KS cases, but detected no additional mutation carriers. Our results suggest STAT4 as a KS predisposing gene. However, further genetic and functional validation is needed to claim causality. Third, a family of four cousins with a rare subtype of Hodgkin lymphoma, namely NLPHL, was studied for genetic predisposition. Linkage analysis and exome sequencing revealed a frameshift mutation (c.2437-2438_delAG) in NPAT segregating with NLPHL in the family. We sequenced NPAT from a large number of HL patients, and detected an in-frame deletion (c.2171-2173delCTT, p.Ser725del) that was more prevalent in cases than in population matched controls (odds ratio 4.11, P=0.018), supporting the role of NPAT as a candidate predisposition gene. Fourth, we studied a family with five affected siblings with intracranial meningiomas, four of whom had multiple meningiomas. We identified a c.367C>T (p.Arg123Cys) mutation in SUFU that segregated with the meningiomas in the family. The tumors from the affected individuals showed loss of heterozygosity of the wild-type allele at the site of the mutation. We showed that the mutation led to lowered SUFU activity and dysregulated Hedgehog signaling. Our genetic and functional analyses indicate that germline SUFU mutations predispose to meningiomas, particularly multiple meningiomas.
  • Vaahtomeri, Kari (Helsingin yliopisto, 2011)
    Tumorigenesis is a consequence of inactivating mutations of tumor suppressor genes and activating mutations of proto-oncogenes. Most of the mutations compromise cell autonomous and non-autonomous restrains on cell proliferation by modulating kinase signal transduction pathways. LKB1 is a tumor suppressor kinase whose sporadic mutations are frequently found in non-small cell lung cancer and cervical cancer. Germ-line mutations in the LKB1 gene lead to Peutz-Jeghers syndrome with an increased risk of cancer and development of benign gastrointestinal hamartomatous polyps consisting of hyperproliferative epithelia and prominent stromal stalk composed of smooth muscle cell lineage cells. The tumor suppressive function of LKB1 is possibly mediated by 14 identified LKB1 substrate kinases, whose activation is dependent on the LKB1 kinase complex. The aim of my thesis was to identify cell signaling pathways crucial for tumor suppression by LKB1. Re-introduction of LKB1 expression in the melanoma cell line G361 induces cell cycle arrest. Here we demonstrated that restoring the cytoplasmic LKB1 was sufficient to induce the cell cycle arrest in a tumor suppressor p53 dependent manner. To address the role of LKB1 in gastrointestinal tumor suppression, Lkb1 was deleted specifically in SMC lineage in vivo, which was sufficient to cause Peutz-Jeghers syndrome type polyposis. Studies on primary myofibroblasts lacking Lkb1 suggest that the regulation of TGFβ signaling, actin stress fibers and smooth muscle cell lineage differentiation are candidate mechanisms for tumor suppression by LKB1 in the gastrointestinal stroma. Further studies with LKB1 substrate kinase NUAK2 in HeLa cells indicate that NUAK2 is part of a positive feedback loop by which NUAK2 expression promotes actin stress fiber formation and, reciprocally the induction of actin stress fibers promote NUAK2 expression. Findings in this thesis suggest that p53 and TGFβ signaling pathways are potential mediators of tumor suppression by LKB1. An indication of NUAK2 in the promotion of actin stress fibers suggests that NUAK2 is one possible mediator of LKB1 dependent TGFβ signaling and smooth muscle cell lineage differentiation.
  • Kyttälä, Mira (Helsingin yliopisto, 2006)
    Meckel syndrome (MKS, MIM 249000) is an autosomal recessive developmental disorder causing death in utero or shortly after birth. The hallmarks of the disease are cystic kidney dysplasia and fibrotic changes of the liver, occipital encephalocele with or without hydrocephalus and polydactyly. Other anomalies frequently seen in the patients are incomplete development of the male genitalia, club feet and cleft lip or palate. The clinical picture has been well characterized in the literature while the molecular pathology underlying the disease has remained unclear until now. In this study we identified the first MKS gene by utilizing the disease haplotypes in Finnish MKS families linked to the MKS1 locus on chromosome 17q23 (MKS1) locus. Subsequently, the genetic heterogeneity of MKS was established in the Finnish families. Mutations in at least four different genes can cause MKS. These genes have been mapped to the chromosomes 17q23 (MKS1), 11q13 (MKS2), 8q22 (MKS3) and 9q33 (MKS4). Two of these genes have been identified so far: The MKS1 gene (this work) and the MKS3 gene. The identified MKS1 gene was initially a novel human gene which is conserved among species. We found three different MKS mutations, one of them being the Finnish founder mutation. The information available from MKS1 orthologs in other species convinced us that the MKS1 gene is required for normal ciliogenesis. Defects of the cilial system in other human diseases and model organisms actually cause phenotypic features similar to those seen in MKS patients. The MKS3 (TMEM67) gene encodes a transmembrane protein and the gene maps to the syntenic Wpk locus in the rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. The available information from these two genes suggest that MKS1 would encode a structural component of the centriole required for normal ciliary functions, and MKS3 would be a transmembrane component most likely required for normal ciliary sensory signaling. The MKS4 locus was localized to chromosme 9q32-33 in this study by using an inbred Finnish family with two affected and two healthy children. This fourth locus contains TRIM32 gene, which is associated to another well characterized human ciliopathy, Bardet Biedl syndrome (BBS). Future studies should identify the MKS4 gene on chromosome 9q and confirm if there are more than two genes causing MKS Finnish families. The research on critical signaling pathways in organogenesis have shown that both Wnt and Hedgehog pathways are dependent on functional cilia. The MKS gene products will serve as excellent model molecules for more detailed studies of the functional role of cilia in organogenesis in more detail.
  • Siintola, Eija (Helsingin yliopisto, 2008)
    The neuronal ceroid lipofuscinoses (NCLs) are a group of mostly autosomal recessively inherited neurodegenerative disorders. The aim of this thesis was to characterize the molecular genetic bases of these, previously genetically undetermined, NCL forms. Congenital NCL is the most aggressive form of NCLs. Previously, a mutation in the cathepsin D (CTSD) gene was shown to cause congenital NCL in sheep. Based on the close resemblance of the phenotypes between congenital NCLs in sheep and human, CTSD was considered as a potential candidate gene in humans as well. When screened for mutations by sequencing, a homozygous nucleotide duplication creating a premature stop codon was identified in CTSD in one family with congenital NCL. While in vitro the overexpressed truncated mutant protein was stable although inactive, the absence of CTSD staining in brain tissue samples of patients indicated degradation of the mutant CTSD in vivo. A lack of CTSD staining was detected also in another, unrelated family with congenital NCL. These results imply that CTSD deficiency underlies congenital NCL. While initially Turkish vLINCL was considered a distinct genetic entity (CLN7), mutations in the CLN8 gene were later reported to account for the disease in a subset of Turkish patients with vLINCL. To further dissect the genetic basis of the disease, all known NCL genes were screened for homozygosity by haplotype analysis of microsatellite markers and/or sequenced in 13 mainly consanguineous, Turkish vLINCL families. Two novel, family-specific homozygous mutations were identified in the CLN6 gene. In the remaining families, all known NCL loci were excluded. To identify novel gene(s) underlying vLINCL, a genomewide single nucleotide polymorphism scan, homozygosity mapping, and positional candidate gene sequencing were performed in ten of these families. On chromosome 4q28.1-q28.2, a novel major facilitator superfamily domain containing 8 (MFSD8) gene with six family-specific homozygous mutations in vLINCL patients was identified. MFSD8 transcript was shown to be ubiquitously expressed with a complex pattern of alternative splicing. Our results suggest that MFSD8 is a novel lysosomal integral membrane protein which, as a member of the major facilitator superfamily, is predicted to function as a transporter. Identification of MFSD8 emphasizes the genetic heterogeneity of Turkish vLINCL. In families where no MFSD8 mutations were detected, additional NCL-causing genes remain to be identified. The identification of CTSD and MFSD8 increases the number of known human NCL-causing genes to eight, and is an important step towards the complete understanding of the genetic spectrum underlying NCLs. In addition, it is a starting point for dissecting the molecular mechanisms behind the associated NCLs and contributes to the challenging task of understanding the molecular pathology underlying the group of NCL disorders.
  • Hodgson, Ulla (Helsingin yliopisto, 2006)
  • Rauta, Virpi (Helsingin yliopisto, 2006)
    IgA nephropathy (IgAN) is the most common primary glomerulonephritis. In one third of the patients the disease progresses, and they eventually need renal replacement therapy. IgAN is in most cases a slowly progressing disease, and the prediction of progression has been difficult, and the results of studies have been conflicting. Henoch-Schönlein nephritis (HSN) is rare in adults, and prediction of the outcome is even more difficult than in IgAN. This study was conducted to evaluate the clinical and histopathological features and predictors of the outcome of IgAN and HSN diagnosed in one centre (313 IgAN patients and 38 HSN patients), and especially in patients with normal renal function at the time of renal biopsy. The study also aimed to evaluate whether there is a difference in the progression rates in four countries (259 patients from Finland, 112 from UK, 121 from Australia and 274 from Canada), and if so, can this be explained by differences in renal biopsy policy. The third aim was to measure urinary excretions of cytokines interleukin 1ß (IL-1ß) and interleukin 1 receptor antagonist (IL-1ra) in patients with IgAN and HSN and the correlations of excretion of these substances with histopathological damage and clinical factors. A large proportion of the patients diagnosed in Helsinki as having IgAN had normal renal function (161/313 patients). Four factors, (hypertension, higher amounts of urinary erythrocytes, severe arteriolosclerosis and a higher glomerular score) which independently predicted progression (logistic regression analysis), were identified in mild disease. There was geographic variability in renal survival in patients with IgAN. When age, levels of renal function, proteinuria and blood pressure were taken into account, it showed that the variability related mostly to lead-time bias and renal biopsy indications. Amount of proteinuria more than 0.4g/24h was the only factor that was significantly related to the progression of HSN. the Hypertension and the level of renal function were found to be factors predicting outcome in patients with normal renal function at the time of diagnosis. In IgAN patients, IL-1ra excretion into urine was found to be decreased as compared with HSN patients and healthy controls. Patients with a high IL-1ra/IL-1ß ratio had milder histopathological changes in renal biopsy than patients with a low/normal IL-1ra/IL-1ß ratio. It was also found that the excretion of IL-1ß and especially IL-1ra were significantly higher in women. In conclusion, it was shown that factors associated with outcome can reliably be identified even in mild cases of IgAN. Predicting outcome in adult HSN, however, remains difficult.
  • Kotiranta-Ainamo, Anna (Helsingin yliopisto, 2006)
    The purpose of this work was to elucidate the ontogeny of interleukin-10 (IL-10) secretion from newborn mononuclear cells (MCs), and to examine its relation to the secretion of interferon-g (IFN-g) and immunoglobulins (Igs). The initial hypothesis was that the decreased immunoglobulin (Ig) synthesis of newborn babies was the result of immature cytokine synthesis regulation, which would lead to excessive IL-10 production, leading in turn to suppressed IFN-g secretion. Altogether 57 full-term newborns and 34 adult volunteers were enrolled. Additionally, surface marker compositions of 29 premature babies were included. Enzyme-linked immunoassays were used to determine the amount of secreted IL-10, IFN-g, and Igs, and the surface marker composition of MC were analyzed with a FACScan flow cytometer. The three most important findings were: 1. Cord blood MC, including CD5+ B cells, are able to secrete IL-10. However, when compared with adults, the secretion of IL-10 was decreased. This indicates that reasons other than excessive IL-10 secretion are responsible of reduced IFN-g secretion in newborns. 2. As illustrated by the IL-10 and IFN-g secretion pattern, newborn cytokine profile was skewed towards the Th2 type. However, approximately 25% of newborns had an adult like cytokine profile with both good IL10 and IFN-g secretion, demonstrating that fullterm newborns are not an immunologically homogenous group at the time of birth. 3. There were significant differences in the surface marker composition of MCs between individual neonates. While gestational age correlated with the proportion of some MC types, it is evident that there are many other maternal and fetal factors that influence the maturity and nature of lymphocyte subpopulations in individual neonates. In conclusion, the reduced ability of neonates to secrete Ig and IFN-g is not a consequence of high IL-10 secretion. However, individual newborns differ significantly in their ability to secrete cytokines as well as Igs.
  • Sinkkonen, Saku (Helsingin yliopisto, 2004)
  • Mustonen, Antti (Helsingin yliopisto, 2009)
    Acute knee injury is a common event throughout life, and it is usually the result of a traffic accident, simple fall, or twisting injury. Over 90% of patients with acute knee injury undergo radiography. An overlooked fracture or delayed diagnosis can lead to poor patient outcome. The major aim of this thesis was retrospectively to study imaging of knee injury with a special focus on tibial plateau fractures in patients referred to a level-one trauma center. Multi-detector computed tomography (MDCT) findings of acute knee trauma were studied and compared to radiography, as well as whether non-contrast MDCT can detect cruciate ligaments with reasonable accuracy. The prevalence, type, and location of meniscal injuries in magnetic resonance imaging (MRI) were evaluated, particularly in order to assess the prevalence of unstable meniscal tears in acute knee trauma with tibial plateau fractures. The possibility to analyze with conventional MRI the signal appearance of menisci repaired with bioabsorbable arrows was also studied. The postoperative use of MDCT was studied in surgically treated tibial plateau fractures: to establish the frequency and indications of MDCT and to assess the common findings and their clinical impact in a level-one trauma hospital. This thesis focused on MDCT and MRI of knee injuries, and radiographs were analyzed when applica-ble. Radiography constitutes the basis for imaging acute knee injury, but MDCT can yield information beyond the capabilities of radiography. Especially in severely injured patients , sufficient radiographs are often difficult to obtain, and in those patients, radiography is unreliable to rule out fractures. MDCT detected intact cruciate ligaments with good specificity, accuracy, and negative predictive value, but the assessment of torn ligaments was unreliable. A total of 36% (14/39) patients with tibial plateau fracture had an unstable meniscal tear in MRI. When a meniscal tear is properly detected preoperatively, treatment can be combined with primary fracture fixation, thus avoiding another operation. The number of meniscal contusions was high. Awareness of the imaging features of this meniscal abnormality can help radiologists increase specificity by avoiding false-positive findings in meniscal tears. Postoperative menisci treated with bioabsorbable arrows showed no difference, among different signal intensities in MRI, among menisci between patients with operated or intact ACL. The highest incidence of menisci with an increased signal intensity extending to the meniscal surface was in patients whose surgery was within the previous 18 months. The results may indicate that a rather long time is necessary for menisci to heal completely after arrow repair. Whether the menisci with an increased signal intensity extending to the meniscal surface represent improper healing or re-tear, or whether this is just the earlier healing feature in the natural process remains unclear, and further prospective studies are needed to clarify this. Postoperative use of MDCT in tibial plateau fractures was rather infrequent even in this large trauma center, but when performed, it revealed clinically significant information, thus benefitting patients in regard to treatment.
  • Manninen, Otto (Helsingin yliopisto, 2015)
    Unverricht-Lundborg type progressive myoclonus epilepsy (EPM1, OMIM 254800) is an autosomal recessive disorder characterized by onset at the age of 6 to 16 years, incapacitating stimulus-sensitive myoclonus and tonic-clonic epileptic seizures. It is caused by mutations in the gene encoding cystatin B (CSTB). However, the disease processes leading to the observed symptoms are currently unclear. Clinical magnetic resonance imaging (MRI) of the brain has shown neurodegenerative changes and computed tomography data have suggested a bone phenotype. This thesis examined the disease processes and the background of the pathological changes in the brain and the bone, utilizing modern imaging methods and image analysis methodology complemented with experimental data in the mouse model (the Cstb -/- mouse) of the disease. In order to gain a comprehensive picture of the disease progression in the brain, we performed a longitudinal imaging study in the Cstb -/- mouse. Animals were studied from the pre-symptomatic to fully symptomatic disease stages (1-6 mo). For studying atrophic changes, in vivo MRI volumetry was preformed once a month from 1 to 6 months of age. For investigating white matter (WM) changes, ex vivo diffusion tensor imaging (DTI) was performed at 2, 4 and 6 months. The fractional anisotropy (FA) maps derived from DTI data were analysed using track based spatial statistics (TBSS) that provided us with a hypothesis-free analysis of white matter changes. In vivo volumetry showed progressive volume loss in Cstb-/- mice over time, the rate of which was neither spatially nor temporally uniform over the brain. TBSS revealed progressing FA decrease, suggesting severe and widespread WM damage, with most drastic changes in the cerebellum and the thalamus. Subsequently the congruence of the observed WM changes between the mouse model and EPM1 patients were evaluated. In vivo DTI data from fully symptomatic adult patients and ex vivo data from fully symptomatic (6 mo) Cstb-/- mice were analysed using TBSS with matching protocols. The results revealed extensive changes with a pattern of chronic WM degeneration in EPM1 patients, with similar alterations detected in Cstb-/- mice. Furthermore, previously unknown brain regions were shown to be affected both in patients and in mice. The imaging data were then used to guide tissue level analyses in mice. The microstructural counterpart of the areas with decreased FA in mice was characterized by immunohistochemistry and transmission electron microscopy. Based on the tissue level findings, the extensive changes identified by DTI in both EPM1 patients and in Cstb-/- mice are probably a consequence of widespread WM loss upon axonal degeneration, and likely contribute to the motor disturbances present in the disease. Finally, we characterized the bone changes underlying the observed skeletal phenotype in EPM1 patients by performing microtomography (µCT), histology, and in vitro cell culture experiments with the Cstb-/- mouse. Analysis of bone microstructure in Cstb-/- mice using μCT revealed structural changes. Moreover, histology confirmed both structural and functional alterations. The basis of these findings was investigated by studying the functionality of bone resorbing osteoclasts differentiated in vitro from bone marrow. In resorption pit formation assays, less and smaller resorption pits were formed by Cstb-/- osteoclasts, indicating decreased resorptive capacity, likely due to a decrease in osteoclast numbers. These data imply that the skeletal changes in Cstb-/- mice and EPM1 patients are a result of CSTB deficiency leading to altered osteoclast function, and the results would indicate that CSTB has a more substantial role as a modulator of bone metabolism than previously thought. Our results showed high correlations of the atrophy, WM and bone phenotypes between EPM1 patients and Cstb-/- mice and provided information about brain and tissue level changes present in these pathologies. High correlation between the mouse model and the findings in patients provided further affirmation for the use of the mouse model in EPM1 research. Furthermore, the results provided new insight both into the progression of brain pathology and the processes underlying the bone changes present in the disease. Finally, our research introduced new methodologies for research in mouse models of neurodegenerative diseases, and raised the prospects of future research.