Molecular background of three lethal fetal syndromes

This study identified the molecular defects underlying three lethal fetal syndromes. Lethal Congenital Contracture Syndrome 1 (LCCS1, MIM 253310) and Lethal Arthrogryposis with Anterior Horn Cell Disease (LAAHD, MIM 611890) are fetal motor neuron diseases. They affect the nerve cells that control voluntary muscle movement, and eventually result in severe atrophy of spinal cord motor neurons and fetal immobility. Both LCCS1 and LAAHD are caused by mutations in the GLE1 gene, which encodes for a multifunctional protein involved in posttranscriptional mRNA processing. LCCS2 and LCCS3, two syndromes that are clinically similar to LCCS1, are caused by defective proteins involved in the synthesis of inositol hexakisphosphate (IP6), an essential cofactor of GLE1. This suggests a common mechanism behind these fetal motor neuron diseases, and along with accumulating evidence from genetic studies of more late-onset motor neuron diseases such as Spinal muscular atrophy (SMA) and Amyotrophic lateral sclerosis (ALS), implicates mRNA processing as a common mechanism in motor neuron disease pathogenesis. We also studied gle1-/- zebrafish in order to investigate whether they would be a good model for studying the pathogenesis of LCCS1 and LAAHD. Mutant zebrafish exhibit cell death in their central nervous system at two days post fertilization, and the distribution of mRNA within the cells of mutant zebrafish differs from controls, encouraging further studies. The third lethal fetal syndrome is described in this study for the first time. Cocoon syndrome (MIM 613630) was discovered in a Finnish family with two affected individuals. Its hallmarks are the encasement of the limbs under the skin, and severe craniofacial abnormalities, including the lack of skull bones. We showed that Cocoon syndrome is caused by a mutation in the gene encoding the conserved helix-loop-helix ubiquitous kinase CHUK, also known as IκB kinase α (IKKα). The mutation results in the complete lack of CHUK protein expression. CHUK is a subunit of the IκB kinase enzyme that inhibits NF-κB transcription factors, but in addition, it has an essential, independent role in controlling keratinocyte differentiation, as well as informing morphogenetic events such as limb and skeletal patterning. CHUK also acts as a tumor suppressor, and is frequently inactivated in cancer. This study has brought significant new information about the molecular background of these three lethal fetal syndromes, as well as provided knowledge about the prerequisites of normal human development.

Urban ecosystem services at the plant-soil interface

Continuing urbanization is a crucial driver of land transformation, having widespread impacts on virtually all ecosystems. Terrestrial ecosystems, including disturbed ones, are dependent on soils, which provide a multitude of ecosystem services. As soils are always directly and/or indirectly impacted through land transformation, land cover change causes soil change. Knowledge of ecosystem properties and functions in soils is increasing in importance as humans continue to concentrate into already densely-populated areas. Urban soils often have hampered functioning due to various disturbances resulting from human activity. Innovative solutions are needed to bring the lacking ecosystem services and quality of life to these urban environments. For instance, the ecosystem services of the urban green infrastructure may be substantially improved through knowledge of their functional properties. In the research forming this thesis, the impacts of four plant species (Picea abies, Calluna vulgaris, Lotus corniculatus and Holcus lanatus) on belowground biota and regulatory ecosystem services were investigated in two different urban soil types. The retention of inorganic nitrogen and phosphorus in the plant-soil system, decomposition of plant litter, primary production, and the degradation of polycyclic aromatic hydrocarbons (PAHs) were examined in the field and under laboratory conditions. The main objective of the research was to determine whether the different plant species (representing traits with varying litter decomposability) will give rise to dissimilar urban belowground communities with differing ecological functions. Microbial activity as well as the abundance of nematodes and enchytraeid worm biomass was highest below the legume L. corniculatus. L. corniculatus and the grass H. lanatus, producing labile or intermediate quality litter, enhanced the proportion of bacteria in the soil rhizosphere, while the recalcitrant litter-producing shrub C. vulgaris and the conifer P. abies stimulated the growth of fungi. The loss of nitrogen from the plant-soil system was small for H. lanatus and the combination of C. vulgaris + P. abies, irrespective of their energy channel composition. These presumably nitrogen-conservative plant species effectively diminished the leaching losses from the plant-soil systems with all the plant traits present. The laboratory experiment revealed a difference in N allocation between the plant traits: C. vulgaris and P. abies sequestered significantly more N in aboveground shoots in comparison to L. corniculatus and H. Lanatus. Plant rhizosphere effects were less clear for phosphorus retention, litter decomposition and the degradation of PAH compounds. This may be due to the relatively short experimental durations, as the maturation of the plant-soil system is likely to take a considerably longer time. The empirical studies of this thesis demonstrated that the soil communities rapidly reflect changes in plant coverage, and this has consequences for the functionality of soils. The energy channel composition of soils can be manipulated through plants, which was also supported by the results of the separate meta-analysis conducted in this thesis. However, further research is needed to understand the linkages between the biological community properties and ecosystem services in strongly human-modified systems.

Electrocardiographic parameters of ventricular repolarization : modifiers and the prognostic value

Electric activity of the heart consists of repeated cardiomyocyte depolarizations and repolarizations. Abnormalities in repolarization predispose to ventricular arrhythmias. In body surface electrocardiogram, ventricular repolarization generates the T wave. Several electrocardiographic measures have been developed both for clinical and research purposes to detect repolarization abnormalities. The study aim was to investigate modifiers of ventricular repolarization with the focus on the relationship of the left ventricular mass, antihypertensive drugs, and common gene variants, to electrocardiographic repolarization parameters. The prognostic value of repolarization parameters was also assessed. The study subjects originated from a population of more than 200 middle-aged hypertensive men attending the GENRES hypertension study, and from an epidemiological survey, the Health 2000 Study, including more than 6000 participants. Ventricular repolarization was analysed from digital standard 12-lead resting electrocardiograms with two QT-interval based repolarization parameters (QT interval, T-wave peak to T-wave end interval) and with a set of four T-wave morphology parameters. The results showed that in hypertensive men, a linear change in repolarization parameters is present even in the normal range of left ventricular mass, and that even mild left ventricular hypertrophy is associated with potentially adverse electrocardiographic repolarization changes. In addition, treatments with losartan, bisoprolol, amlodipine, and hydrochlorothiazide have divergent short-term effects on repolarization parameters in hypertensive men. Analyses of the general population sample showed that single nucleotide polymorphisms in KCNH2, KCNE1, and NOS1AP genes are associated with changes in QT-interval based repolarization parameters but not consistently with T-wave morphology parameters. T-wave morphology parameters, but not QT interval or T-wave peak to T-wave end interval, provided independent prognostic information on mortality. The prognostic value was specifically related to cardiovascular mortality. The results indicate that, in hypertension, altered ventricular repolarization is already present in mild left ventricular mass increase, and that commonly used antihypertensive drugs may relatively rapidly and treatment-specifically modify electrocardiographic repolarization parameters. Common variants in cardiac ion channel genes and NOS1AP gene may also modify repolarization-related arrhythmia vulnerability. In the general population, T-wave morphology parameters may be useful in the risk assessment of cardiovascular mortality.

Despairing Justice and the Ethics of Legal Interpretation

This study discusses legal interpretation. The question is how legal texts, for instance laws, statutes and regulations, can and do have meaning. Language makes interpretation difficult as it holds no definite meanings. When the theoretical connection between semantics and legal meaning is loosened and we realise that language cannot be a means of justifying legal decisions, the responsibility inherent in legal interpretation can be seen in full. We are thus compelled to search for ways to analyse this responsibility. The main argument of the book is that the responsibility of legal interpretation contains a responsibility towards the text that is interpreted (and through the mediation of the text also towards the legal system), but not only this. It is not simply a responsibility to read and read well, but it transcends on a broader scale. It includes responsibility for the effects of the interpretation in a particular situation and with regard to the people whose case is decided. Ultimately, it is a responsibility to do justice. These two aspects of responsibility are conceptualised here as the two dimensions of the ethics of legal interpretation: the textual and the situational. The basic conception of language presented here is provided by Ludwig Wittgenstein s later philosophy, but the argument is not committed to only one philosophical tradition. Wittgenstein can be counterpointed in interesting ways by Jacques Derrida s ideas on language and meaning. Derrida s work also functions as a contrast to hermeneutic theories. It is argued that the seed to an answer to the question of meaning lies in the inter-personal and situated activity of interpretation and communication, an idea that can be discerned in different ways in the works of Wittgenstein, Derrida and Hans-Georg Gadamer. This way the question of meaning naturally leads us to think about ethics, which is approached here through the philosophy of Emmanuel Levinas. His thinking, focusing on topics such as otherness, friendship and hospitality, provides possibilities for answering some of the questions posed in this book. However, at the same time we move inside a normativity where ethics and politics come together in many ways. The responsibility of legal interpretation is connected to the political and this has to be acknowledged lest we forget that law always implies force. But it is argued here that the political can be explored in positive terms as it does not have to mean only power or violence.

Cognitive functioning and its heritability in bipolar I disorder

Bipolar I disorder is a severe psychiatric disorder characterized by episodic mood alterations that can be manic, depressive or mixed. Bipolar disorder seems to be highly genetic, but the etiology of this complex disorder has remained elusive. In recent years, studies have found that euthymic patients with bipolar disorder may have impairments particularly in executive functioning, verbal learning and memory. These impairments may be present also among some of the relatives of these patients, who may be vulnerable to the disorder. Using neuropsychological variables as endophenotypes, i.e. intermediate phenotypes between genes and the phenotypes, has been suggested to aid search for the etiological background of the disorder, but evidence is sparse on whether these variables fulfill the criteria for endophenotypes. The present thesis is part of the Genetic Epidemiology and Molecular Genetics of Severe Mental Disorders in Finland project. The specific aim was to investigate whether neuropsychological test variables would indicate genetic liability to the disorder and could therefore be regarded as endophenotypes. Thus, cognitive functions and their heritability were studied in bipolar I disorder patients and in their unaffected first-degree relatives from a population-based sample of families, comparing them to a population-based control group. In order to add homogeneity to the subgroups of bipolar disorder patients and their relatives, cognitive functions and their heritability were further studied in a group of families affected by bipolar I disorder only (bipolar families) and another group of families affected by both bipolar I disorder and schizophrenia or schizoaffective disorders (mixed families). Finally, the effect of processing speed on other cognitive functions was investigated. The study showed that especially executive functioning and processing speed fulfilled the endophenotype criteria. Impairments in these functions were found in bipolar patients and in their relatives irrespective of other severe psychopathology in the family. These functions were highly heritable in these families. Study also showed that generalized impairment in verbal memory may associate more with bipolar disorder than to vulnerability to other psychotic disorders, and be more related to fully developed disease; impairments in verbal learning and memory were found only in patients, and they were not found to be highly heritable. Finally, the most potential endophenotype, i.e. processing speed, seemed to contribute to a range of other cognitive dysfunctions seen in bipolar disorder patients. Processing speed, in particular, has also been shown to be a valid endophenotype in subsequent association analyses in psychiatric genetics in Finland and internationally. Information concerning cognitive impairments and their association with the psychosocial consequences of bipolar disorder is important in planning treatment. It is also important to understand and acknowledge that patients may have cognitive impairments that affect their everyday life. Psychosocial interventions and neuropsychological rehabilitation may supplement other conventional treatments for bipolar patients.

Identification of molecules relevant for the invasiveness of fibrosarcomas and melanomas

Cancer is becoming the leading cause of deaths in the world. As 90% of all deaths from cancer are caused by metastasis, discovery of the mechanisms behind cancer cell invasion and metastasis is of utmost importance. Only new effective therapies targeting cancer progression can reduce cancer mortality rates. The aim of this study was to identify molecules that are relevant for tumor cell invasion and spreading in fibrosarcomas and melanomas, and to analyze their potential for cancer biomarkers or therapeutic targets. First, the gene expression changes of normal cells and transformed cells showing high invasiveness, S-adenosylmethionine decarboxylase (AdoMetDC)-transfected murine fibroblasts and human melanoma cells, were studied by microarray analyses. The function of the identified candidate molecules were then studied in detail in these cell lines. Finally, the physiological relevance of the identified changes was studied by immunohistochemical analyses of human sarcoma and melanoma specimens or by a mouse xenograft model. In fibrosarcoma cells, the most remarkable change detected was a dramatic up-regulation of the actin-sequestering molecule thymosin beta 4 (TB4), which was shown to be important for the transformed phenotype of the AdoMetDC-transfected cells (Amdc-s and -as). A sponge toxin latrunculin A, inhibiting the binding of TB4 to actin, was found to selectively inhibit the migration and invasion of these cells. Further, Amdc-s-induced mouse tumors and human high-grade sarcomas were found to show intense TB4 immunostaining. In addition to TB4, integrin subunits alfa 6 and beta 7 (ItgA6 and ItgB7) were found to be up-regulated in Amdc-s and -as cells. ItgA6 was shown to dimerize mainly with ItgB1 in Amdc-s. Inhibition of ItgA6 or ItgB1 function with neutralizing antibodies fully blocked the invasiveness of Amdc-s cells, and importantly also human HT-1080 fibrosarcoma cells, in three-dimensional (3D)-Matrigel mimicking tumor extracellular matrix (ECM). By immunohistochemical analyses, strong staining for ITGA6 was detected in human high-grade fibrosarcomas and other sarcomas, especially at the invasion fronts of the tumors. In the studied melanoma cell lines, the expression levels of the adhesion-related ECM proteins tenascin-C (TN-C), fibronectin (FN), and transforming growth factor beta-induced (TGFBI) were found to be highly up-regulated. By immunohistochemistry, intense TN-C and FN staining was detected in invasive and metastatic melanoma tumors, showing co-localization (together with procollagen-I) in tubular meshworks and channels around the invading melanoma cells. In vitro, TN-C and FN were further found to directly stimulate the migration of melanoma cells in 3D-collagen-I matrix. The third candidate protein, TGFBI, was found to be an anti-adhesive molecule for melanoma cells, and knockdown of its expression in metastatic melanoma cells (TGFBI-KD cells) led to dramatically impaired tumor growth in immunocompromized mice. Interestingly, the control tumors showed intense TGFBI immunostaining in the invasion fronts, showing partial co-localization with the fibrillar FN staining, whereas the small TGFBI-KD cell-induced tumors displayed amorphous, non-fibrillar FN staining. These data suggest an important role for TGFBI in FN fibrillogenesis and melanoma progression. In conclusion, we have identified several invasion-related molecules, which show potential for cancer diagnostic or prognostic markers, or therapeutic targets. Based on our previous and present fibrosarcoma studies, we propose the possibility of using ITGA6 antagonists (affecting tumor cell adhesion) in combination with TB4 inhibitors (affecting tumor cell migration) and cathepsin L inhibitors (affecting the degradation of basement membrane and ECM proteins) for the treatment of fibrosarcomas and other tumors overexpressing these molecules. With melanoma cells, in turn, we point to the importance of three secreted ECM proteins, TN-C, FN, and TGFBI, in melanoma progression. Of these, especially the potential of TN-C as a prognostic melanoma biomarker and TGFBI as a promising therapeutic target molecule are clearly worth additional studies.

Merkel cell carcinoma : Epidemiological study with special reference to polyomavirus and vascular factors in pathogenesis

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy that occurs predominantly on sun exposed skin areas. A new polyomavirus (MCPyV) was identified in MCC tumor tissues in 2008 suggesting that a viral infection might be an etiological factor. A typical MCC is a rapidly growing painless purple nodule. In its early stage it can be misjudged by its appearance as a cyst or abscess. Recurrences are common and approximately half of the patients will develop lymph node metastases and third of the patents will have distant metastases. It affects mostly elderly persons at an average age of 70 at the time of diagnosis. MCC was first described in 1972 and the first MCC patient in Finland was identified in 1983. MCC has been poorly recognized, but increased awareness and better diagnostic accuracy has increased the incidence since the early years. In this study, all cases with a notation of MCC during 1979 2008 were obtained from the Finnish Cancer Registry. Based on this data, the incidence is 0.11 for men and 0.12 for women. It is similar than that of other Nordic countries, but lower than in the USA. For clinical series, the files of patients diagnosed with MCC during 1983 2004 were reviewed, and the tissue samples were re-evaluated, if available (n=181). Third of the patients were men, and the most common site of the primary tumor was the head and neck (53%). The majority of the patients (86%) presented with a clinically node-negative (Stage I or II) disease, but the disease recurred in 38% of them. The treatment schemes were heterogeneous. No additional benefit from a wide margin (≥2 cm) was found compared to a margin of 0.1-1.9 cm, but intralesional excision was more often associated with local recurrence. None of the patients with Stage I-II disease who had received postoperative radiotherapy had local recurrence during the follow-up period. The 5-year relative survival ratio for Stage I disease was 68%, for Stage II 67%, for Stage III 16%, and for Stage IV 0%. The relative excess risk of death was significantly lower among women than among men. Some of these tissue samples were further analyzed for vascular invasion (n=126) by immunohistochemistry using vascular endothelial markers CD-31 and D2-40. Vascular invasion was seen in 93% of the samples and it was observed already in very small, <5mm tumors. The tissue samples were also analyzed for the presence of MCPyV by using a polymerase chain reaction (PCR) and quantitative PCR. MCPyV DNA was present in 80% of 114 samples studied. The patients with virus-positive tumors had better overall survival than patients with virus-negative tumors. Immunohistochemical analyses were performed for the expression of VEGFR-2 (n=21) and endostatin (n=19), but they had no prognostic value. Our results support the concept of treating MCC with margin-negative excision and radiotherapy to the tumor bed to reduce local recurrence. The finding of a high frequency of lymphovascular invasion reduces its value as a prognostic factor, but emphasizes the role of sentinel node biopsy even in very small primary MCC.

Many Faces of Mao Zedong

The main aim of this work was to explore the use of Mao Zedong s (毛泽东, 1893—1976) visual image in contemporary Chinese art during the years 1976—2006. Chairman Mao is the most visually reproduced person in the People's Republic of China (PRC), and the presence of his image is still unquestionable at many levels. Although several scholars have provided insightful observations on this topic, research focusing on Mao's visual image has been neglected. Employing the interdisciplinary approach of visual studies and using image as the main concept, this research combines different theoretical frameworks, deriving from art history, image studies and social sciences, for each chapter in order to explain the origins, intentions and major strategies of the contemporary Chinese artists. The focus of this research was to elucidate how Mao's visual image, deriving from the Maoist era, is re-created and negotiated in contemporary Chinese art works. The material reproductions - the visual images in contemporary art - are created to be juxtaposed with the immaterial mental images of Mao that were created during the Maoist era through the original visual images of Mao. This complex interaction between visual and mental images is further exemplified by art works that do not include Mao's visual image, but still imply his mental image. The methods used derive from both sinology and art history. The research is based on extensive fieldwork in China, which was crucial for gathering new information and materials from this vigorous art scene. The topic is approached through a Chinese cultural, political and historical perspective that is necessary for a further understanding of how the original visual images of Mao obtained their omnipotent status and what kind of iconography was created. Close structural analysis, taking into account the format, style, techniques, composition, colors, materials and space used in the art works, is employed to demonstrate the great variety of visual images created. The analysis is further placed in a continuous dialogue both with the contemporary art works of Mao and with the original visual images of Mao from the past. In this study it is shown that contemporary Chinese art relating to Chairman Mao is a more versatile and multilayered phenomenon than is generally assumed. Although some of the art works seem to fit into the definition of superficial art, the study demonstrates that this reading of the art works is not adequate. The author argues that employing Mao's visual images in contemporary Chinese art is based on three main strategies used by artists: to create a visual dialogue with a traumatizing past, to employ transcontextual parody, and to explore the importance of Tian'anmen through site-dependent art. These strategies are not exclusionary, but instead interdependent and many art works employ more than one of them. In addition, these three main strategies include versatile methods used by artists that make the use of Mao's visual images even more multifaceted.

Magnetic resonance imaging and ultrasonography in brachial plexus birth injury

Brachial plexus birth injury (BPBI) is caused by stretching, tearing or avulsion of the C5-C8 or Th1 nerve roots during delivery. Foetal-maternal disproportion is the main reason for BPBI. The goal of this study was to find out the incidence of posterior subluxation of the humeral head during first year of life in BPBI and optimal timing of the ultrasonographic screening of the glenohumeral joint. The glenohumeral congruity and posterior subluxation of the humeral head associated to muscle atrophy were assessed and surgical treatment of the shoulder girdle as well as muscle changes in elbow flexion contracture were evaluated. The prospective, population based part of the study included all neonates born in Helsinki area during years 2003-2006. Patients with BPBI sent to the Hospital for Children and Adolescents because of decreased external rotation, internal rotation contracture or deformation of the glenohumeral joint as well as patients with elbow flexion contracture were also included in this prospective study. The incidence of BPBI was calculated to be 3.1/1000 newborns in Helsinki area. About 80% of the patients with BPBI recover totally during the follow-up within the first year of life. Permanent plexus injury at the age of one year was noted in 20% of the patients (0.64/1000 newborns). Muscle imbalance resulted in sonographically detected posterior subluxation in one third of the patients with permanent BPBI. If muscle imbalance and posterior subluxation are left untreated bony deformities will develop. All patients with internal rotation contracture of the glenohumeral joint presented muscle atrophy of the rotator cuff muscles. Especially subscapular and infraspinous muscles were affected. A correlation was found particularly between greatest thickness of subscapular muscle and subluxation of the humeral head, degree of glenoid retroversion, as well as amount of internal rotation contracture. Supinator muscle atrophy was evident among all the studied patients with elbow flexion contracture. Brachial muscle pathology seemed to be an important factor for elbow flexion contracture in BPBI. Residual dysfunction of the upper extremity may require operative treatment such as tendon lengthening, tendon transfers, relocation of the humeral head or osteotomy of the humerus. Relocation of the humeral head improved the glenohumeral congruency among patients under 5 years of age. Functional improvement without remodeling of the glenohumeral joint was achieved by other reconstructive procedures. In conclusion: Shoulder screening by US should be done to all patients with permanent BPBI at the age of 3 and 6 months. Especially atrophy of the subscapular muscle correlates with glenohumeral deformity and posterior subluxation of the humeral head, which has not been reported in previous studies. Permanent muscle changes are the main reason for diminished range of motion of the elbow and forearm. Relocation of the humeral head, when needed, should be performed under the age of 5 years.

Towards Optimal Testing of Auditory Memory : Methodological development of recording of the mismatch negativity (MMN) of the auditory event-related potential (ERP)

The overlapping sound pressure waves that enter our brain via the ears and auditory nerves must be organized into a coherent percept. Modelling the regularities of the auditory environment and detecting unexpected changes in these regularities, even in the absence of attention, is a necessary prerequisite for orientating towards significant information as well as speech perception and communication, for instance. The processing of auditory information, in particular the detection of changes in the regularities of the auditory input, gives rise to neural activity in the brain that is seen as a mismatch negativity (MMN) response of the event-related potential (ERP) recorded by electroencephalography (EEG). --- As the recording of MMN requires neither a subject s behavioural response nor attention towards the sounds, it can be done even with subjects with problems in communicating or difficulties in performing a discrimination task, for example, from aphasic and comatose patients, newborns, and even fetuses. Thus with MMN one can follow the evolution of central auditory processing from the very early, often critical stages of development, and also in subjects who cannot be examined with the more traditional behavioural measures of auditory discrimination. Indeed, recent studies show that central auditory processing, as indicated by MMN, is affected in different clinical populations, such as schizophrenics, as well as during normal aging and abnormal childhood development. Moreover, the processing of auditory information can be selectively impaired for certain auditory attributes (e.g., sound duration, frequency) and can also depend on the context of the sound changes (e.g., speech or non-speech). Although its advantages over behavioral measures are undeniable, a major obstacle to the larger-scale routine use of the MMN method, especially in clinical settings, is the relatively long duration of its measurement. Typically, approximately 15 minutes of recording time is needed for measuring the MMN for a single auditory attribute. Recording a complete central auditory processing profile consisting of several auditory attributes would thus require from one hour to several hours. In this research, I have contributed to the development of new fast multi-attribute MMN recording paradigms in which several types and magnitudes of sound changes are presented in both speech and non-speech contexts in order to obtain a comprehensive profile of auditory sensory memory and discrimination accuracy in a short measurement time (altogether approximately 15 min for 5 auditory attributes). The speed of the paradigms makes them highly attractive for clinical research, their reliability brings fidelity to longitudinal studies, and the language context is especially suitable for studies on language impairments such as dyslexia and aphasia. In addition I have presented an even more ecological paradigm, and more importantly, an interesting result in view of the theory of MMN where the MMN responses are recorded entirely without a repetitive standard tone. All in all, these paradigms contribute to the development of the theory of auditory perception, and increase the feasibility of MMN recordings in both basic and clinical research. Moreover, they have already proven useful in studying for instance dyslexia, Asperger syndrome and schizophrenia.

Vastasyntyneen varsan sepsis osa II - Infektion diagnosoiminen, aiheuttajamikrobit ja mikrobilääkeresistenssi

Sepsis eli infektion aiheuttama yleistynyt tulehdusreaktio on merkittävä kuolleisuuden aiheuttaja vastasyntyneillä varsoilla. Kirjallisuuskatsauksessa on käsitelty sepsiksen patofysiologiaa ja kliinisiä oireita vastasyntyneillä varsoilla sekä sepsikselle altistavia tekijöitä. Vastasyntyneen varsan sepsiksen diagnosoimisessa kliinisten oireiden arvioinnilla on keskeinen merkitys sairauden varhaisessa tunnistamisessa ja hoidon aloittamisessa. Sairauden nopean etenemisen ja veriviljelytulosten hitaan valmistumisen vuoksi antibioottihoito joudutaan aloittamaan jo ennen viljelytulosten valmistumista. Veriviljelyllä on kuitenkin tärkeä merkitys sepsisdiagnoosin ja valitun antibioottihoidon varmistamisessa. Sairaalakohtaisten veriviljelynäytetulosten seuranta mahdollistaa ensisijaisen mikrobilääkkeen valinnan aiemmin eristettyjen aiheuttajamikrobien esiintyvyyden ja mikrobilääkeherkkyyksien perusteella. Yleisimpiä vastasyntyneen varsan sepsiksen aiheuttajia ovat kirjallisuuden mukaan suolistoperäiset gram-negatiiviset bakteerit. Escherichia colin osuus vastasyntyneiltä varsoilta otetuista veriviljelynäytteistä eristetyistä bakteerikannoista on vaihdellut eri tutkimuksissa 18,7 - 50,0 %. Pohjois-Amerikassa tehdyissä tutkimuksissa varsojen veriviljelynäytteistä eristettyjen E.coli -kantojen herkkyys yleisesti käytetylle trimetopriimi-sulfadiatsiinille on ollut huono (57–71 %). Penisilliinin ja gentamisiinin yhdistelmälle enterobakteerien herkkyyden on raportoitu olevan hyvä. Suomessa tilanteen on arvioitu olevan parempi. Tutkimuksessa kartoitettiin retrospektiivisesti veriviljelyn käyttöä varsojen sepsiksen diagnostiikassa, sepsiksen aiheuttajamikrobien esiintymistä ja mikrobilääkkeiden käyttöä Yliopistollisessa eläinsairaalassa (YES) vuosina 2004–2006. Tutkimusaineisto koostuu yhteensä 90 korkeintaan 10 päivän ikäisenä YES:aan tuodun varsan potilastiedoista. Sairaalaan saapuneista varsoista 30 % oli otettu veriviljelynäyte. Veriviljelynäytteistä positiivisia oli 62,5 %. 60 % positiivisista näytteistä kasvoi vähintään kahta bakteerilajia. Yleisin aiheuttajabakteeri oli Escherichia coli (23,1 %). Yksi eristetyistä E.coli -kannoista oli resistentti ampisilliinille, gentamisiinille ja trimetopriimi-sulfadiatsiinille. Aineiston pienen koon vuoksi tutkimus ei kuitenkaan anna luotettavaa kuvaa eristettyjen aiheuttajamikrobien mikrobilääkeherkkyydestä laajemmin. Sekakasvujen osuus oli suuri ja tyypillisten veriviljelynäytteitä kontaminoivien bakteerilajien (Streptococcus viridans sp., Micrococcus sp., koagulaasinegatiiviset stafylokokit) osuus oli yli 30 % eristetyistä bakteerikannoista. Tämä viittaa ongelmiin veriviljelynäytteenottotekniikassa riittävän aseptiikan saavuttamien osalta. Koagulaasinegatiiviset stafylokokit voivat myös aiheuttaa sepsiksen, mutta niiden merkitys vastasyntyneiden varsojen sepsiksen aiheuttajina on epäselvä.

Excimer laser refractive surgery : corneal wound healing and clinical results

Although the first procedure in a seeing human eye using excimer laser was reported in 1988 (McDonald et al. 1989, O'Connor et al. 2006) just three studies (Kymionis et al. 2007, O'Connor et al. 2006, Rajan et al. 2004) with a follow-up over ten years had been published when this thesis was started. The present thesis aims to investigate 1) the long-term outcomes of excimer laser refractive surgery performed for myopia and/or astigmatism by photorefractive keratectomy (PRK) and laser-in situ- keratomileusis (LASIK), 2) the possible differences in postoperative outcomes and complications when moderate-to-high astigmatism is treated with PRK or LASIK, 3) the presence of irregular astigmatism that depend exclusively on the corneal epithelium, and 4) the role of corneal nerve recovery in corneal wound healing in PRK enhancement. Our results revealed that in long-term the number of eyes that achieved uncorrected visual acuity (UCVA)≤0.0 and ≤0.5 (logMAR) was higher after PRK than after LASIK. Postoperative stability was slightly better after PRK than after LASIK. In LASIK treated eyes the incidence of myopic regression was more pronounced when the intended correction was over >6.0 D and in patients aged <30 years.Yet the intended corrections in our study were higher for LASIK than for PRK eyes. No differences were found in percentages of eyes with best corrected visual acuity (BCVA) or loss of two or more lines of visual acuity between PRK and LASIK in the long-term. The postoperative long-term outcomes of PRK with two different delivery systems broad beam and scanning laser were compared and revealed no differences. Postoperative outcomes of moderate-to-high astigmatism yielded better results in terms of UCVA and less compromise or loss of two more lines of BCVA after LASIK that after PRK.Similar stability for both procedures was revealed. Vector analysis showed that LASIK outcomes tended to be more accurate than PRK outcomes, yet no statistically differences were found. Irregular astigmatism secondary to recurrent corneal erosion due to map-dot-fingerprint was successfully treated with phototherapeutic keratectomy (PTK). Preoperative videokeratographies (VK) showed irregular astigmatism. However, postoperatively, all eyes showed a regular pattern. No correlation was found between pre- and postoperative VK patterns. Postoperative outcomes of late PRK in eyes originally subjected to LASIK showed that all (7/7) eyes achieved UCVA ≤0.5 at last follow-up (range 3 — 11 months), and no eye lost lines of BCVA. Postoperatively all eyes developed and initial mild haze (0.5 — 1) into the first month. Yet, at last follow-up 5/7 eyes showed a haze of 0.5 and this was no longer evident in 2/7 eyes. Based on these results, we demonstrated that the long-term outcomes after PRK and LASIK were safe and efficient, with similar stability for both procedures. The PRK outcomes were similar when treated by broad-beam or scanning slit laser. LASIK was better than PRK to correct moderate-to-high astigmatism, yet both procedures showed a tendency of undercorrection. Irregular astigmatism was proven to be able to depend exclusively from the corneal epithelium. If this kind of astigmatism is present in the cornea and a customized PRK/LASIK correction is done based on wavefront measurements an irregular astigmatism may be produced rather than treated. Corneal sensory nerve recovery should have an important role in the modulation of the corneal wound healing and post-operative anterior stromal scarring. PRK enhancement may be an option in eyes with previous LASIK after a sufficient time interval that in at least 2 years.

Micropillar Array Based Microchips for Electrospray Ionization Mass Spectrometry, Microreactors, and Liquid Chromatographic Separation

This dissertation deals with the design, fabrication, and applications of microscale electrospray ionization chips for mass spectrometry. The microchip consists of microchannel, which leads to a sharp electrospray tip. Microchannel contain micropillars that facilitate a powerful capillary action in the channels. The capillary action delivers the liquid sample to the electrospray tip, which sprays the liquid sample to gas phase ions that can be analyzed with mass spectrometry. The microchip uses a high voltage, which can be utilized as a valve between the microchip and mass spectrometry. The microchips can be used in various applications, such as for analyses of drugs, proteins, peptides, or metabolites. The microchip works without pumps for liquid transfer, is usable for rapid analyses, and is sensitive. The characteristics of performance of the single microchips are studied and a rotating multitip version of the microchips are designed and fabricated. It is possible to use the microchip also as a microreactor and reaction products can be detected online with mass spectrometry. This property can be utilized for protein identification for example. Proteins can be digested enzymatically on-chip and reaction products, which are in this case peptides, can be detected with mass spectrometry. Because reactions occur faster in a microscale due to shorter diffusion lengths, the amount of protein can be very low, which is a benefit of the method. The microchip is well suited to surface activated reactions because of a high surface-to-volume ratio due to a dense micropillar array. For example, titanium dioxide nanolayer on the micropillar array combined with UV radiation produces photocatalytic reactions which can be used for mimicking drug metabolism biotransformation reactions. Rapid mimicking with the microchip eases the detection of possibly toxic compounds in preclinical research and therefore could speed up the research of new drugs. A micropillar array chip can also be utilized in the fabrication of liquid chromatographic columns. Precisely ordered micropillar arrays offer a very homogenous column, where separation of compounds has been demonstrated by using both laser induced fluorescence and mass spectrometry. Because of small dimensions on the microchip, the integrated microchip based liquid chromatography electrospray microchip is especially well suited to low sample concentrations. Overall, this work demonstrates that the designed and fabricated silicon/glass three dimensionally sharp electrospray tip is unique and facilitates stable ion spray for mass spectrometry.

The Politics and Policies of Reproductive Agency

This study examines the politics and policies of reproductive agency through a redescription of three Finnish policy documents dealing with the declining birth rate: the Government report on the future 'Finland for people of all ages' (2004), Business and Policy Forum EVA report 'Condemned to Diminish?' (Tuomitut vähenemään?) (2003), and the Family Federation's 'Population Policy Program' (2004). The redescription is done with the help of the notion of reproductive agency, which draws on Drucilla Cornell's concepts of the imaginary domain and bodily integrity. The imaginary domain is the moral and psychic space people need in order to form their personality, which is created in constant identificatory processes. The aim of the processes is imaginary coherence. As the personality is embodied, forming one s imaginary coherence always includes attempts for bodily integrity, also entailing attempts to arrive at an understanding of one's procreative capacities. Besides Cornell, I draw on Judith Butler's thinking and comprehend gender performatively as doing, and in relation to that agency as part of the performative process of one's personality. Reproductive agency is understood in this study as the possibilities to live differently the hegemonic forms of procreative life. I deal with three redescriptive themes: the family, economics and gender. The family is a central element in that it is considered the main location of reproduction. With regard to reproductive agency, the documents include problematic conceptions of the family. It is defined as a heterosexual, monogamous, conjugal relationship, which affects reproductive agency in that these notions do not allow for different modes of family life. The second prominent aspect, economics, features on two levels: the macroeconomic level of GDP, employment and competitiveness, and the level of family policies and concern about family finances. Macroeconomic-level argumentation is problematic in the context of reproductive agency because it implies that procreation is a duty of citizens, and thus has effects on values attached to reproductive potential. On the other hand, family policies may advance reproductive agency in supporting families financially. However, such policies also define how the family is understood, thereby affecting reproductive agency. The third theme, gender, intersects with many issues in the policy documents. All three texts consider the roles of men and women differently: women are primarily responsible for the family, and both men's and women's reproductive agency is affected in that the roles in the procreative process are predefined. EVA and the Family Federation see women as the main target of population policies, and consider it legitimate to try to change women s reproductive decisions. Implicit in the notion of reproductive agency is the idea that it should be possible to overcome and live differently the sex difference, but the three documents do not open up opportunities for that. The notion of reproductive agency makes it also possible to question the legitimacy of population policies in general and offers new perspectives on the vocabularies used in the three policy texts, providing insights into the values and logics that support the concepts.

Seerumin kreatiinikinaasi- ja aspartaattiaminotransferaasiaktiivisuuden vaikutus kalkkunoiden (Meleagris gallopavo) käyttäytymiseen erikorkuisissa kuljetushäkeissä

Kalkkunoiden teuraskuljetuksissa lintuja pidetään kuljetuspäällyksissä, joiden korkeuden on esitetty olevan riittämätön suurimpien kalkkunakukkojen kuljetukseen, mutta tieteellisiä tutkimuksia aiheesta on vähän. Jalostuksella saavutetut nopeakasvuiset ja suuret lihakset voivat lisäksi altistaa kalkkunat mahdollisesti kivuliaille lihassairauksille. Tutkielman tavoitteena oli selvittää lihasentsyymiarvojen vaikutusta kalkkunoiden käyttäytymiseen erikorkuisissa kuljetuspäällyksissä. Tutkimuksessa analysoitiin kreatiinikinaasin (CK) ja aspartaattiaminotransferaasin (ASAT) aktiivisuutta kalkkunoiden seerumissa, sillä näiden solunsisäisten entsyymien yhtäaikainen esiintyminen seerumissa on todettu olevan merkki lihasvauriosta ja täten kuvaavan eläimen heikentynyttä hyvinvointia. Tutkimuksessa käytettiin 36 lihantuotantoon jalostettua kalkkunakukkoa. Kutakin lintua testattiin kahtena eri päivänä noin viikon välein. Testattavien lintujen paino oli keskimäärin 16,5 ± 0,2 kiloa. Linnut olivat eri testikerroilla satunnaistetusti erikorkuisissa häkeissä. Häkkikorkeudet olivat 40, 55 ja 90 cm. Linnut olivat paikallaan olevissa häkeissä kuusi tuntia, jonka ajan niiden käyttäytymistä videoitiin. Kustakin linnusta otettiin verinäyte yhdellä testauskerralla kuvaamisen päätyttyä ja seerumista analysoitiin CK ja ASAT. Kalkkunoiden CK-aktiivisuus oli 25450,5 ±10402,6 IU/l ja ASAT-aktiivisuus 625,0 ±143,7 IU/l. Häkkikorkeudella ei ollut tilastollisesti merkitsevää korrelaatiota CK- eikä ASAT-aktiivisuuden kanssa (p = 0,86 ja p = 0,68), mutta CK- ja ASAT-arvot korreloivat positiivisesti keskenään (p < 0,001). Sekä CK- että ASAT-aktiivisuuksien ollessa korkeat linnut makasivat vähemmän 55 cm ja 90 cm korkeissa häkeissä testijakson ensimmäisinä tunteina. Paino ja CK-aktiivisuus olivat positiivisesti korreloituneet (p = 0,001). Kalkkunoiden lihasentsyymiarvoista on saatavilla heikosti tietoa, mutta verrattuna moniin muihin eläinlajeihin kalkkunoiden seerumin CK- ja ASAT-arvot ovat huomattavan korkeat. 40 cm korkeissa häkeissä linnut eivät voineet tilan ahtauden vuoksi seistä normaalissa asennossa jalat ojennettuina kuten muissa häkkikorkeuksissa. Linnuilla kivun liittymistä lihassairauksiin ei ole kuvattu, mutta kipu on varsin todennäköistä akuutissa vaiheessa. Kalkkunat siis saattavat mahdollisuuksien mukaan välttää makaamista kivun vuoksi. Jalostuksella saatu rintalihaksen nopea kasvu suhteettoman suureksi on todettu voivan aiheuttaa lihasvaurioita. On mahdollista, että jo suuri koko itsessään saattaa aiheuttaa kalkkunoille kipua. Tekijät, jotka kohottavat seerumin lihasentsyymiarvoja, aiheuttavat joka tapauksessa myös hyvinvointiongelmia. Nykyisin käytössä olevat matalat, 40 cm korkeat, kuljetuspäällykset voivat heikentää etenkin suurikokoisten kalkkunakukkojen kuljetuksen aikaista hyvinvointia, koska ne estävät lintuja seisomasta luonnollisessa asennossa ja niissä liikkuminen on muutenkin hyvin rajoitettua. Jotta jalostettujen kalkkunoiden lihasentsyymiarvoista voitaisiin tehdä tarkempia johtopäätöksiä, tarvitaan lisää tutkimuksia lihasentsyymiarvojen perustason määrittämiseksi. Lisätutkimuksia tarvitaan myös kalkkunoiden mahdollisesti kokeman kivun ja lihasentsyymiarvojen välisestä yhteydestä.