Ischemic Stroke in Young Adults

Stroke is the second leading cause of death and the leading cause of disability worldwide. Of all strokes, up to 80% to 85% are ischemic, and of these, less than 10% occur in young individuals. Stroke in young adults—most often defined as stroke occurring under the age of 45 or 50—can be particularly devastating due to long expected life-span ahead and marked socio-economic consequences. Current basic knowledge on ischemic stroke in this age group originates mostly from rather small and imprecise patient series. Regarding emergency treatment, systematic data on use of intravenous thrombolysis are absent. For this Thesis project, we collected detailed clinical and radiological data on all consecutive patients aged 15 to 49 with first-ever ischemic stroke between 1994 and 2007 treated at the Helsinki University Central Hospital. The aims of the study were to define demographic characteristics, risk factors, imaging features, etiology, and long-term mortality and its predictors in this patient population. We additionally sought to investigate, whether intravenous thrombolysis is safe and beneficial for the treatment of acute ischemic stroke in the young. Of our 1008 patients, most were males (ratio 1.7:1), who clearly outnumbered females after the age of 44, but females were preponderant among those aged <30. Occurrence increased exponentially. The most frequent risk factors were dyslipidemia (60%), smoking (44%), and hypertension (39%). Risk factors accumulated in males and along aging. Cardioembolism (20%) and cervicocerebral artery dissection (15%) were the most frequent etiologic subgroups, followed by small-vessel disease (14%), and large-artery atherosclerosis (8%). A total of 33% had undetermined etiology. Left hemisphere strokes were more common in general. Posterior circulation infarcts were more common among those aged <45. Multiple brain infarcts were present in 23% of our patients, 13% had silent infarcts, and 5% had leukoaraiosis. Of those with silent brain infarcts, majority (54%) had only a single lesion, and most of the silent strokes were located in basal ganglia (39%) and subcortical regions (21%). In a logistic regression analysis, type 1 diabetes mellitus in particular predicted the presence of both silent brain infarcts (odds ratio 5.78, 95% confidence interval 2.37-14.10) and leukoaraiosis (9.75; 3.39-28.04). We identified 48 young patients with hemispheric ischemic stroke treated with intravenous tissue plasminogen activator, alteplase. For comparisons, we searched 96 untreated control patients matched by age, gender, and admission stroke severity, as well as 96 alteplase-treated older controls aged 50 to 79 matched by gender and stroke severity. Alteplase-treated young patients recovered more often completely (27% versus 10%, P=0.010) or had only mild residual symptoms (40% versus 22%, P=0.025) compared to age-matched controls. None of the alteplase-treated young patients had symptomatic intracerebral hemorrhage or died within 3-month follow-up. Overall long-term mortality was low in our patient population. Cumulative mortality risks were 2.7% (95% confidence interval 1.5-3.9%) at 1 month, 4.7% (3.1-6.3%) at 1 year, and 10.7% (9.9-11.5%) at 5 years. Among the 30-day survivors who died during the 5-year follow-up, more than half died due to vascular causes. Malignancy, heart failure, heavy drinking, preceding infection, type 1 diabetes, increasing age, and large-artery atherosclerosis causing the index stroke independently predicted 5-year mortality when adjusted for age, gender, relevant risk factors, stroke severity, and etiologic subtype. In sum, young adults with ischemic stroke have distinct demographic patterns and they frequently harbor traditional vascular risk factors. Etiology in the young is extremely diverse, but in as many as one-third the exact cause remains unknown. Silent brain infarcts and leukoaraiosis are not uncommon brain imaging findings in these patients and should not be overlooked due to their potential prognostic relevance. Outcomes in young adults with hemispheric ischemic stroke can safely be improved with intravenous thrombolysis. Furthermore, despite their overall low risk of death after ischemic stroke, several easily recognizable factors—of which most are modifiable—predict higher mortality in the long term in young adults.

Timing of puberty : Genetic regulation

In the general population, the timing of puberty is normally distributed. This variation is determined by genetic and environmental factors, but the exact mechanisms underlying these influences remain elusive. The purpose of this study was to gain insight into genetic regulation of pubertal timing. Contributions of genetic versus environmental factors to the normal variation of pubertal timing were explored in twins. Familial occurrence and inheritance patterns of constitutional delay of growth and puberty, CDGP (a variant of normal pubertal timing), were studied in pedigrees of patients with this condition. To ultimately detect genes involved in the regulation of pubertal timing, genetic loci conferring susceptibility to CDGP were mapped by linkage analysis in the same family cohort. To subdivide the overall phenotypic variance of pubertal timing into genetic and environmental components, genetic modeling based on monozygous twins sharing 100% and dizygous twins sharing 50% of their genes was used in 2309 girls and 1828 boys from the FinnTwin 12-17 study. The timing of puberty was estimated from height growth, i.e. change in the relative height between the age when pubertal growth velocity peaks in the general population and adulthood. This reflects the percentage of adult height achieved at the average peak height velocity age, and thus, pubertal timing. Boys and girls diagnosed with CDGP were gathered through medical records from six pediatric clinics in Finland. First-degree relatives of the probands were invited to participate by letter; altogether, 286 families were recruited. When possible, families were extended to include also second-, third-, or fourth-degree relatives. The timing of puberty in all family members was primarily assessed from longitudinal growth data. Delayed puberty was defined by onset of pubertal growth spurt or peak height velocity taking place 1.5 (relaxed criterion) or 2 SD (strict criterion) beyond the mean. If growth data were unavailable, pubertal timing was based on interviews. In this case, CDGP criteria were set as having undergone pubertal development more than 2 (strict criterion) or 1.5 years (relaxed criterion) later than their peers, or menarche after 15 (strict criterion) or 14 years (relaxed criterion). Familial occurrence of strict CDGP was explored in families of 124 patients (95 males and 29 females) from two clinics in Southern Finland. In linkage analysis, we used relaxed CDGP criteria; 52 families with solely growth data-based CDGP diagnoses were selected from all clinics. Based on twin data, genetic factors explain 86% and 82% of the variance of pubertal timing in girls and boys, respectively. In families, 80% of male and 76% of female probands had affected first-degree relatives, in whom CDGP was 15 times more common than the expected (2.5%). In 74% (17 of 23) of the extended families with only one affected parent, familial patterns were consistent with autosomal dominant inheritance. By using 383 multiallelic markers and subsequently fine-mapping with 25 additional markers, significant linkage for CDGP was detected to the pericentromeric region of chromosome 2, to 2p13-2q13 (multipoint HLOD 4.44, α 0.41). The findings of the large twin study imply that the vast majority of the normal variation of pubertal timing is attributed to genetic effects. Moreover, the high frequency of dominant inheritance patterns and the large number of affected relatives of CDGP patients suggest that genetic factors also markedly contribute to constitutional delay of puberty. Detection of the locus 2p13-2q13 in the pericentromeric region of chromosome 2 associating with CDGP is one step towards unraveling the genes that determine pubertal timing.

Carotid Stenosis, Endarterectomy, and the Brain : Brain microcirculation, diffusion, and cognitive function before and after carotid endarterectomy in patients with a high-grade carotid stenosis

Carotid atherosclerotic disease is a major cause of stroke, but it may remain clinically asymptomatic. The factors that turn the asymptomatic plaque into a symptomatic one are not fully understood, neither are the subtle effects that a high-grade carotid stenosis may have on the brain. The purpose of this study was to evaluate brain microcirculation, diffusion, and cognitive performance in patients with a high-grade stenosis in carotid artery, clinically either symptomatic or asymptomatic, undergoing carotid endarterectomy (CEA). We wanted to find out whether the stenoses are associated with diffusion or perfusion abnormalities of the brain or variation in the cognitive functioning of the patients, and to what extent the potential findings are affected by CEA, and compare the clinically symptomatic and asymptomatic subjects as well as strictly healthy controls. Coagulation and fibrinolytic parameters were compared with the rate microembolic signals (MES) in transcranial Doppler (TCD) and the macroscopic appearance of stenosing plaques in surgery. Patients (n=92) underwent CEA within the study. Blood samples pertaining to coagulation and fibrinolysis were collected before CEA, and the subjects underwent repeated TCD monitoring for MES. A subpopulation (n= 46) underwent MR imaging and repeated neuropsychological examination (preoperative, as well 4 and 100 days after CEA). In MRI, the average apparent diffusion coefficients were higher in the ipsilateral white matter (WM), and altough the interhemispheric difference was abolished by CEA, the levels remained higher than in controls. Symptomatic stenoses were associated with more sluggish perfusion especially in WM, and lower pulsatility of flow in TCD. All patients had poorer cognitive performance than healthy controls. Cognitive functions improved as expected by learning effect despite transient postoperative worsening in a few subjects. Improvement was greater in patients with deepest hypoperfusion, primarily in executive functions. Symptomatic stenoses were associated with higher hematocrit and tissue plasminogen activator antigen levels, as well as higher rate of MES and ulcerated plaques, and better postoperative improvement of vasoreactivity and pulsatility. In light of the findings, carotid stenosis is associated with differences in brain diffusion, perfusion, and cognition. The effect on diffusion in the ipsilateral WM, partially reversible by CEA, may be associated with WM degeneration. Asymptomatic and symptomatic subpopulations differ from each other in terms of hemodynamic adaptation and in their vascular physiological response to removal of stenosis. Although CEA may be associated with a transient cognitive decline, a true improvement of cognitive performance by CEA is possible in patients with the most pronounced perfusion deficits. Mediators of fibrinolysis and unfavourable hemorheology may contribute to the development of a symptomatic disease in patients with a high-grade stenosis.

Effects of Metabolic Risk Factors and Type 1 Diabetes on Brain Glucose and Brain Metabolites

The metabolic syndrome and type 1 diabetes are associated with brain alterations such as cognitive decline brain infarctions, atrophy, and white matter lesions. Despite the importance of these alterations, their pathomechanism is still poorly understood. This study was conducted to investigate brain glucose and metabolites in healthy individuals with an increased cardiovascular risk and in patients with type 1 diabetes in order to discover more information on the nature of the known brain alterations. We studied 43 20- to 45-year-old men. Study I compared two groups of non-diabetic men, one with an accumulation of cardiovascular risk factors and another without. Studies II to IV compared men with type 1 diabetes (duration of diabetes 6.7 ± 5.2 years, no microvascular complications) with non-diabetic men. Brain glucose, N-acetylaspartate (NAA), total creatine (tCr), choline, and myo-inositol (mI) were quantified with proton magnetic resonance spectroscopy in three cerebral regions: frontal cortex, frontal white matter, thalamus, and in cerebellar white matter. Data collection was performed for all participants during fasting glycemia and in a subgroup (Studies III and IV), also during a hyperglycemic clamp that increased plasma glucose concentration by 12 mmol/l. In non-diabetic men, the brain glucose concentration correlated linearly with plasma glucose concentration. The cardiovascular risk group (Study I) had a 13% higher plasma glucose concentration than the control group, but no difference in thalamic glucose content. The risk group thus had lower thalamic glucose content than expected. They also had 17% increased tCr (marker of oxidative metabolism). In the control group, tCr correlated with thalamic glucose content, but in the risk group, tCr correlated instead with fasting plasma glucose and 2-h plasma glucose concentration in the oral glucose tolerance test. Risk factors of the metabolic syndrome, most importantly insulin resistance, may thus influence brain metabolism. During fasting glycemia (Study II), regional variation in the cerebral glucose levels appeared in the non-diabetic subjects but not in those with diabetes. In diabetic patients, excess glucose had accumulated predominantly in the white matter where the metabolite alterations were also the most pronounced. Compared to the controls values, the white matter NAA (marker of neuronal metabolism) was 6% lower and mI (glia cell marker) 20% higher. Hyperglycemia is therefore a potent risk factor for diabetic brain disease and the metabolic brain alterations may appear even before any peripheral microvascular complications are detectable. During acute hyperglycemia (Study III), the increase in cerebral glucose content in the patients with type 1 diabetes was, dependent on brain region, between 1.1 and 2.0 mmol/l. An every-day hyperglycemic episode in a diabetic patient may therefore as much as double brain glucose concentration. While chronic hyperglycemia had led to accumulation of glucose in the white matter, acute hyperglycemia burdened predominantly the gray matter. Acute hyperglycemia also revealed that chronic fluctuation in blood glucose may be associated with alterations in glucose uptake or in metabolism in the thalamus. The cerebellar white matter appeared very differently from the cerebral (Study IV). In the non-diabetic men it contained twice as much glucose as the cerebrum. Diabetes had altered neither its glucose content nor the brain metabolites. The cerebellum seems therefore more resistant to the effects of hyperglycemia than is the cerebrum.

Affected sibling pairs with juvenile idiopathic arthritis : An immunogenetic study of the disease in multicase families

Genetic susceptibility to juvenile idiopathic arthritis (JIA) was studied in the genetically homogeneous Finnish population by collecting families with two or three patients affected by this disease from cases seen in the Rheumatism Foundation Hospital. The number of families ranged in different studies from 37 to 45 and the total number of patients with JIA, from among whom these cases were derived, was 2 000 to 2 300. Characteristics of the disease in affected siblings in Finland were compared with a population-based series and with a sibling series from the United States. A thorough clinical and ophthalmological examination was made of all affected patients belonging to sibpair series. Information on the occurrence of chronic rheumatic diseases in parents was collected by questionnaire and diagnoses were confirmed from hospital records. All patients, their parents and most of the healthy sibs were typed for human leukocyte antigen (HLA) alleles in loci A, C, B, DR and DQ. The HLA allele distribution of the cases was compared with corresponding data from Finnish bone marrow donors. The genetic component in JIA was found to be more significant than previously believed. A concordance rate of 25% for a disease with a population prevalence of 1 per 1000 implied a relative risk of 250 for a monozygotic (MZ) twin. An estimate for the sibling risk of an affected individual was about 15- to 20-fold. The disease was basically similar in familial and sporadic cases; the mean age at disease onset was however lower in familial cases, (4.8 years vs 7.4 years). Three sibpairs (3.4 expected) were concordant for the presence of asymptomatic uveitis. Uveitis would thus not appear to have any genetic component of its own, separate from the genetic basis of JIA. Four of the parents had JIA (0.2 cases expected), four had a type of rheumatoid factor-negative arthritis similar to that seen in juvenile patients but commencing in adulthood, and one had spondyloarthropathy (SPA). These findings provide additional support for the conception of a genetic predisposition to JIA and suggest the existence of a new disease entity, JIA of adult onset. Both the linkage analysis of the affected sibpairs and the association analysis of nuclear families provided overwhelming evidence of a major contribution of HLA to the genetic susceptibility to JIA. The association analysis in the Finnish population confirmed that the most significant associations prevailed for DRB1*0801, DQB1*0402, as expected from previous observations, and indicated the independent role of Cw*0401.

Primary Dislocation of the Patella : A Clinical Study

A total of 177 patients with primary dislocation of the patella (PDP) were admitted to two trauma centers in Helsinki, Finland during 1991 to 1992. The inclusion criteria were: 1. Acute (≤14 days old) first-time lateral dislocation of the patella. 2. No previous knee operations or major knee injuries. 3. No ligament injuries to be repaired. 4. No osteochondral fractures requiring fixation. 50 patients were excluded. 30 of these excluded patients would have met the inclusion criteria, 19 patients received treatment by consultants not involved in the study, 7 refused to participate and 4 had an erroneous randomization. 127 patients including, 82 females, were then randomized to have either tailor-made operative procedure (group O) or conservative treatment (group C). The aftercare was similar for both groups. The mean age of the patients was 20 (9-47) years. All patients were subjected to analysis of trauma history (starting position and knee movement during the dislocation), examination under anesthesia (EUA) and arthroscopy. 70 patients (52 females) were randomized by their odd year of birth to operative group O and 57 patients (30 females) by their even year of birth to conservative group C. The diagnosis of PDP was based on locked dislocation in 68 patients, on dislocatability in EUA in 47 patients, and on subluxation in EUA combined with typical intra-articular lesions in 12 patients. In group O, 63 patients had exploration of the injuries on the medial side of the knee and tailor made reconstruction added with lateral release in 54 cases. The medial injury was operated by suturing in 39 patients, by duplication in 18 patients and by additional augmentation of the medial patellofemoral ligament (MPFL) with adductor magnus tenodesis in 6 patients. 7 patients, without locking in trauma history and only subluxation in EUA had only lateral release for realignment. In adductor magnus tenodesis the proximal end of the distal tendinous part was rerouted to the upper medial border of the patella. In the conservative group C, the treatment was adjusted to the extent of patellar displacement in EUA. Patients with dislocation in EUA had 3 weeks’ immobilization with the knee in slight flexion. Mobilization was started with a soft patellar stabilizing orthosis (PSO) used for additional three weeks. The patients with subluxation in EUA wore an orthosis for six weeks. The aftercare was similar in group O. The outcome was similar in both groups. After an average of 25 (20-45) months´ follow-up, the subjective result was better in group C in respect of the mean Hughston VAS knee score (87 for group O and 90 for group C, p=0.04, visual analog scale), but similar in terms of the patient’s own overall opinion and the mean Lysholm II knee score. Recurrent instability episodes occurred in 18 patients in group O and in 20 patients in group C. After an average of 7 (6-9) years´ follow-up, the groups did not show statistical difference either in respect of the patient’s own overall opinion, or the mean Hughston VAS and Kujala knee scores. The proportions of stable patellae was 25/70 (36%) in group O and 17/57 (30%) in group O (p=0.5). In a multivariate risk analysis, there was a correlation between low Kujala score (<90) as dependent parameter and female gender (OR: 3.5; 95% CI: 1.4-9.0), and loose body on primary radiographs (OR: 4.1; 95% CI: 1.2-15). Recurrent instability correlated with young age at the time of PDP (OR: 0.9; 95% CI: 0.8-1.0/year). Girls with open tibial apophysis had the worst prognosis for instability (88%; 95% CI: 77-98). The most common mechanisms in trauma history of the patients were movement to flexion from a straight start (78%) and movement to extension from a well-bent start (8%). Spontaneous relocation of the patella had taken place in 13/39 of girls, in 11/21 of boys, in 26/42 of women and in 17/24 of men with skeletal maturity of the tibia. The dislocation in EUA was non-rotating in 96/126 patients followed by outward rotating dislocation in 14/126 patients. Operative treatment policy in PDP is not recommended. Locking tendency of the patella in PDP depended on the skeletal maturation. Recurrence rate after PDP was higher than expected.

Myoblast transplantation and adenoviral VEGF-C transfer in porcine model of coronary artery disease

Heart failure is a common and highly challenging medical disorder. The progressive increase of elderly population is expected to further reflect in heart failure incidence. Recent progress in cell transplantation therapy has provided a conceptual alternative for treatment of heart failure. Despite improved medical treatment and operative possibilities, end-stage coronary artery disease present a great medical challenge. It has been estimated that therapeutic angiogenesis would be the next major advance in the treatment of ischaemic heart disease. Gene transfer to augment neovascularization could be beneficial for such patients. We employed a porcine model to evaluate the angiogenic effect of vascular endothelial growth factor (VEGF)-C gene transfer. Ameroid-generated myocardial ischemia was produced and adenovirus encoding (ad)VEGF-C or β-galactosidase (LacZ) gene therapy was given intramyocardially during progressive coronary stenosis. Angiography, positron emission tomography (PET), single photon emission computed tomography (SPECT) and histology evidenced beneficial affects of the adVEGF-C gene transfer compared to adLacZ. The myocardial deterioration during progressive coronary stenosis seen in the control group was restrained in the treatment group. We observed an uneven occlusion rate of the coronary vessels with Ameroid constrictor. We developed a simple methodological improvement of Ameroid model by ligating of the Ameroid–stenosed coronary vessel. Improvement of the model was seen by a more reliable occlusion rate of the vessel concerned and a formation of a rather constant myocardial infarction. We assessed the spontaneous healing of the left ventricle (LV) in this new model by SPECT, PET, MRI, and angiography. Significant spontaneous improvement of myocardial perfusion and function was seen as well as diminishment of scar volume. Histologically more microvessels were seen in the border area of the lesion. Double staining of the myocytes in mitosis indicated more cardiomyocyte regeneration at the remote area of the lesion. The potential of autologous myoblast transplantation after ischaemia and infarction of porcine heart was evaluated. After ligation of stenosed coronary artery, autologous myoblast transplantation or control medium was directly injected into the myocardium at the lesion area. Assessed by MRI, improvement of diastolic function was seen in the myoblast-transplanted animals, but not in the control animals. Systolic function remained unchanged in both groups.

Late results after paediatric cardiac surgery

Background: Congenital heart defects include a wide range of inborn malformations. Depending on the defect, the life expectancy of a newborn with cardiac anomaly varies from a few days to a normal life span. In most instances surgery, is the only treatment available. The late results of surgery have not been comprehensively investigated. Aims: Mortality, morbidity and the life situation of all Finnish patients who had been operated on for congenital heart defect during childhood were investigated. Methods: Patient and surgical data were gathered from all hospitals that had performed heart surgeries on children. Late mortality and survival data were obtained from the population registry, and the causes of deaths from Statistics Finland. Morbidity of patients operated on during 1953-1989 was assessed by the usage of medicines. The pharmacotherapy data of patients and controls were obtained from the Social Insurance Institute. The life situation of patients was surveyed by mailed questionnaire. Survival, causes of deaths and life situation of patients were compared with those of the general population. Results: A total of 7240 cardiac operations were performed on 6461 children during the first 37 years of cardiac surgery (1953-1989). The number of procedures constantly rose during this period, and the increase continued in later years. The patient material varied over time, as more defects became surgically treatable. During 1953-1989 the operative mortality (death within 30 days of surgery) was 6.9%. In the 1990s a slight rise occurred in early mortality, as increasingly complicated patients were surgically treated. During 2000-2003 practically no defects were beyond the operative range. Thus, the operative mortality of 4.4% was excellent, decreasing even further to 2.0% in 2004-2007. The overall 45-year survival of patients operated on in 1953-1989 was 78%, and the corresponding figure for the general population was 93%. Survival depended on the defect, being worst among patients with univentricular heart. Late survival was also better during the 1990s and at the beginning of the 21st century. Of the 6028 early survivors, 592 died late (>30 days) after surgery. A total of 397 deaths (67%) were related and 185 (31%) unrelated to congenital heart defect. The cause of death was unknown in 10 cases. Of those 5774 patients who survived their first operation and had complete follow-up, 16% were operated on several times. Seventeen percent of patients used medicines for cardiac symptoms (heart failure, arrhythmia, hypertension and coronary disease). Patients risk of using cardiac medicines was 2.16 (Cl 1.97-2.37) times higher than that of controls. Patients also had more genetic syndromes and mental retardation and more often used medicines for asthma and epilepsy. Adult patients who had been operated on as children had coped surprisingly well with their defects. Their level of education was similar and their employment level even higher than expected, and they were living in a steady relationship as often as the general population. Conclusions: Cardiac surgery developed rapidly, and nowadays practically all defects can be treated. The overall survival of all operated patients was 78%, 16% less than that of the general population. However, it was significantly better than the anticipated natural survival. However, many patients had health problems; 16% needed reoperations and 17% cardiac medicines to maintain their condition. Most of the patients assessed their general health as good and lived a normal life.

Long-term results of obstetric brachial plexus surgery

Background: Brachial plexus birth palsy (BPBP) most often occurs as a result of foetal-maternal disproportion. The C5 and C6 nerve roots of the brachial plexus are most frequently affected. In contrast, roots from the C7 to Th1 that result in total injury together with C5 and C6 injury, are affected in fewer than half of the patients. BPBP was first described by Smellie in 1764. Erb published his classical description of the injury in 1874 and his name became linked with the paralysis that is associated with upper root injury. Since then, early results of brachial plexus surgery have been reasonably well documented. However, from a clinical point of view not all primary results are maintained and there is also a need for later follow-up results. In addition most of the studies that are published emanate from highly specialized clinics and no nation wide epidemiological reports are available. One of the plexus injuries is the avulsion type, in which the nerve root or roots are ruptured at the neural cord. It has been speculated whether this might cause injury to the whole neural system or whether shoulder asymmetry and upper limb inequality results in postural deformities of the spine. Alternatively, avulsion could manifest as other signs and symptoms of the whole musculoskeletal system. In addition, there is no available information covering activities of daily living after obstetric brachial plexus surgery. Patients and methods: This was a population-based cross-sectional study on all patients who had undergone brachial plexus surgery with at least 5 years of follow-up. An incidence of 3.05/1000 for BPBP was obtained from the registers for this study period. A total of 1706 BPBP patients needing hospital treatment out of 1 717 057 newborns were registered in Finland between 1971 and 1997 inclusive. Of these BPBP patients, 124 (7.3%) underwent brachial plexus surgery at a mean age of 2.8 months (range: 0.4―13.2 months). Surgery was most often performed by direct neuroraphy after neuroma resection (53%). Depending on the phase of the study, 105 to 112 patients (85-90%) participated in a clinical and radiological follow-up assessment. The mean follow up time exceeded 13 years (range: 5.0―31.5 years). Functional status of the upper extremity was evaluated using Mallet, Gilbert and Raimondi scales. Isometric strength of the upper limb, sensation of the hand and stereognosis were evaluated for both the affected and unaffected sides then the differences and their ratios were calculated and recorded. In addition to the upper extremity, assessment of the spine and lower extremities were performed. Activities of daily living (ADL), participation in normal physical activities, and the use of physiotherapy and occupational therapy were recorded in a questionnaire. Results: The unaffected limb functioned as the dominant hand in all, except four patients. The mean length of the affected upper limb was 6 cm (range: 1-13.5 cm) shorter in 106 (95%) patients. Shoulder function was recorded as a mean Mallet score of 3 (range: 2―4) which was moderate. Both elbow function and hand function were good. The mean Gilbert elbow scale value was 3 (range: -1―5) and the mean Raimondi hand scale was 4 (range:1―5). One-third of the patients experienced pain in the affected limb including all those patients (n=9) who had clavicular non-union resulting from surgery. A total of 61 patients (57%) had an active shoulder external rotation of less than 0° and an active elbow extension deficiency was noted in 82 patients (77%) giving a mean of 26° (range: 5°―80°). In all, expect two patients, shoulder external rotation strength at a mean ratio 35% (range: 0―83%) and in all patients elbow flexion strength at a mean ratio of 41% (range: 0―79%) were impaired compared to the unaffected side. According to radiographs, incongruence of the glenohumeral joint was noted in 15 (16%) patients, whereas incongruence of the radiohumeral joint was found in 20 (21%) patients. Fine sensation was normal for 34/49 (69%) patients with C5-6 injury, for 15/31 (48%) with C5-7 and for only 8/25 (32%) of patients with total injury. Loss of protective sensation or absent sensation was noted in some palmar areas of the hand for 12/105 patients (11%). Normal stereognosis was recorded for 88/105 patients (84%). No significant inequalities in leg length were found and the incidence of structural scoliosis (1.7%) did not differ from that of the reference population. Nearly half of the patients (43%) had asynchronous motion of the upper limbs during gait, which was associated with impaired upper limb function. Data obtained from the completed questionnaires indicated that two thirds (63%) of the patients were satisfied with the functional outcome of the affected hand although one third of all patients needed help with ADL. Only a few patients were unable to participate in physical activities such as: bicycling, cross-country skiing or swimming. However, 71% of the patients reported problems related to the affected upper limb, such as muscle weakness and/or joint stiffness during the aforementioned activities. Incongruity of the radiohumeral joints, extent of the injury, avulsion type injury, age less than three months of age at the time of plexus surgery and inexperience of the surgeon was related to poor results as determined by multivariate analyses. Conclusions: Most of the patients had persistent sequelae, especially of shoulder function. Almost all measurements for the total injury group were poorer compared with those of the C5-6 type injury group. Most of the patients had asymmetry of the shoulder region and a shorter affected upper limb, which is a probable reason for having an abnormal gait. However, BPBP did not have an effect on normal growth of the lower extremities or the spine. Although, participation in physical activities was similar to that of the normal population, two-thirds of the patients reported problems. One-third of the patients needed help with ADL. During the period covered by this study, 7.3% BPBP of patients that needed hospital treatment had a brachial plexus operation, which amounts to fewer than 10 operations per year in Finland. It seems that better results of obstetric plexus surgery and more careful follow-up including opportunities for late reconstructive procedures will be expected, if the treatment is solely concentrated on by a few specialised teams.

Primary Fallopian tube carcinoma:occurrence, risk and prognostic factors

The aim of the study was to clarify the occurrence, and etiological and prognostic factors of primary fallopian tube carcinoma (PFTC). We studied the sociodemographic determinants of the incidence of PFTC in Finland and the role of chlamydial infections and human papillomavirus infections as risk factors for PFTC. Serum tumor markers were studied as prognostic factors for PFTC. We also evaluated selected reproductive factors (parity, sterilization and hysterectomy) as risk or protective factors of PFTC. The risks of second primary cancers after PFTC were also studied. The age-adjusted incidence of PFTC in Finland increased to 5.4 / 1,000,000 in 1993 97. The incidence rate was higher in the cities, but the relative rise was higher in rural areas. Women in the two highest social classes showed a 1.8 fold incidence compared with those in the lowest. Women in agriculture and those not working outside the home showed only half the PFTC incidence of those in higher socioeconomic occupations. Pretreatment serum concentrations of hCGβ, CA125 and TATI were evaluated as prognostic markers for PFTC. Elevated hCGβ values (above the 75th percentile, 3.5 pmol/L; OR 2.49, 95% CI 1.22 5.09), stage and histology were strong independent prognostic factors for PFTC. The effects of parity, sterilization and hysterectomy on the risk of PFTC were studied in a case control-study with 573 PFTC cases from the Finnish Cancer Registry. In multivariate analysis parity was the only significant protective factor as regards PFTC, with increasing protection associated with increasing number of deliveries. In univariate analysis sterilization gave borderline protection against PFTC and the protective effect increased with time since the operation. In multivariate analysis the protection did not reach statistical significance. Chlamydial and human papillomavirus (HPV) infections were studied in two separate seroepidemiological case-control studies with 78 PFTC patients. The incidence of women with positive HPV or chlamydial serology was the same in PFTC patients and in the control group and was not found to be a risk factor for PFTC. Finally, the possible risk of a second primary cancer after diagnosis and treatment of PFTC in a cohort of 2084 cases from 13 cancer registries followed for second primary cancers within the period 1943 2000 was studied. In PFTC patients, second primary cancers were 36% more common than expected (SIR 1.36, 95% CI 1.13 1.63). In conclusion, the incidence of PFTC has increased in Finland, especially in higher social classes and among those in certain occupations. Elevated serum hCGβ reflect a worsened prognosis. Parity is a clear protective factor, as is previous sterilization. After PFTC there is a risk of second primary cancers, especially colorectal, breast, lung and bladder cancers and non-lymphoid leukemia. The excess of colorectal and breast cancers after PFTC may indicate common effects of earlier treatments, or they could reflect common effects of lifestyle or genetic, immunological or environmental background.

Search for a Light Higgs Boson in Central Exclusive Diffraction: Method and Detectors

By detecting leading protons produced in the Central Exclusive Diffractive process, p+p → p+X+p, one can measure the missing mass, and scan for possible new particle states such as the Higgs boson. This process augments - in a model independent way - the standard methods for new particle searches at the Large Hadron Collider (LHC) and will allow detailed analyses of the produced central system, such as the spin-parity properties of the Higgs boson. The exclusive central diffractive process makes possible precision studies of gluons at the LHC and complements the physics scenarios foreseen at the next e+e− linear collider. This thesis first presents the conclusions of the first systematic analysis of the expected precision measurement of the leading proton momentum and the accuracy of the reconstructed missing mass. In this initial analysis, the scattered protons are tracked along the LHC beam line and the uncertainties expected in beam transport and detection of the scattered leading protons are accounted for. The main focus of the thesis is in developing the necessary radiation hard precision detector technology for coping with the extremely demanding experimental environment of the LHC. This will be achieved by using a 3D silicon detector design, which in addition to the radiation hardness of up to 5×10^15 neutrons/cm2, offers properties such as a high signal-to- noise ratio, fast signal response to radiation and sensitivity close to the very edge of the detector. This work reports on the development of a novel semi-3D detector design that simplifies the 3D fabrication process, but conserves the necessary properties of the 3D detector design required in the LHC and in other imaging applications.

Electromagnetic signatures of lightning near the HF frequency band

The dissertation deals with remote narrowband measurements of the electromagnetic radiation emitted by lightning flashes. A lightning flash consists of a number of sub-processes. The return stroke, which transfers electrical charge from the thundercloud to to the ground, is electromagnetically an impulsive wideband process; that is, it emits radiation at most frequencies in the electromagnetic spectrum, but its duration is only some tens of microseconds. Before and after the return stroke, multiple sub-processes redistribute electrical charges within the thundercloud. These sub-processes can last for tens to hundreds of milliseconds, many orders of magnitude longer than the return stroke. Each sub-process causes radiation with specific time-domain characteristics, having maxima at different frequencies. Thus, if the radiation is measured at a single narrow frequency band, it is difficult to identify the sub-processes, and some sub-processes can be missed altogether. However, narrowband detectors are simple to design and miniaturize. In particular, near the High Frequency band (High Frequency, 3 MHz to 30 MHz), ordinary shortwave radios can, in principle, be used as detectors. This dissertation utilizes a prototype detector which is essentially a handheld AM radio receiver. Measurements were made in Scandinavia, and several independent data sources were used to identify lightning sub-processes, as well as the distance to each individual flash. It is shown that multiple sub-processes radiate strongly near the HF band. The return stroke usually radiates intensely, but it cannot be reliably identified from the time-domain signal alone. This means that a narrowband measurement is best used to characterize the energy of the radiation integrated over the whole flash, without attempting to identify individual processes. The dissertation analyzes the conditions under which this integrated energy can be used to estimate the distance to the flash. It is shown that flash-by-flash variations are large, but the integrated energy is very sensitive to changes in the distance, dropping as approximately the inverse cube root of the distance. Flashes can, in principle, be detected at distances of more than 100 km, but since the ground conductivity can vary, ranging accuracy drops dramatically at distances larger than 20 km. These limitations mean that individual flashes cannot be ranged accurately using a single narrowband detector, and the useful range is limited to 30 kilometers at the most. Nevertheless, simple statistical corrections are developed, which enable an accurate estimate of the distance to the closest edge of an active storm cell, as well as the approach speed. The results of the dissertation could therefore have practical applications in real-time short-range lightning detection and warning systems.

Spin and relativistic motion of bound states

The wave functions of moving bound states may be expected to contract in the direction of motion, in analogy to a rigid rod in classical special relativity, when the constituents are at equal (ordinary) time. Indeed, the Lorentz contraction of wave functions is often appealed to in qualitative discussions. However, only few field theory studies exist of equal-time wave functions in motion. In this thesis I use the Bethe-Salpeter formalism to study the wave function of a weakly bound state such as a hydrogen atom or positronium in a general frame. The wave function of the e^-e^+ component of positronium indeed turns out to Lorentz contract both in 1+1 and in 3+1 dimensional quantum electrodynamics, whereas the next-to-leading e^-e^+\gamma Fock component of the 3+1 dimensional theory deviates from classical contraction. The second topic of this thesis concerns single spin asymmetries measured in scattering on polarized bound states. Such spin asymmetries have so far mainly been analyzed using the twist expansion of perturbative QCD. I note that QCD vacuum effects may give rise to a helicity flip in the soft rescattering of the struck quark, and that this would cause a nonvanishing spin asymmetry in \ell p^\uparrow -> \ell' + \pi + X in the Bjorken limit. An analogous asymmetry may arise in p p^\uparrow -> \pi + X from Pomeron-Odderon interference, if the Odderon has a helicity-flip coupling. Finally, I study the possibility that the large single spin asymmetry observed in p p^\uparrow -> \pi(x_F,k_\perp) + X when the pion carries a high momentum fraction x_F of the polarized proton momentum arises from coherent effects involving the entire polarized bound state.

Ionosphere-atmosphere interaction during solar proton events

Among the most striking natural phenomena affecting ozone are solar proton events (SPE), during which high-energy protons precipitate into the middle atmosphere in the polar regions. Ionisation caused by the protons results in changes in the lower ionosphere, and in production of neutral odd nitrogen and odd hydrogen species which then destroy ozone in well-known catalytic chemical reaction chains. Large SPEs are able to decrease the ozone concentration of upper stratosphere and mesosphere, but are not expected to significantly affect the ozone layer at 15--30~km altitude. In this work we have used the Sodankylä Ion and Neutral Chemistry Model (SIC) in studies of the short-term effects caused by SPEs. The model results were found to be in a good agreement with ionospheric observations from incoherent scatter radars, riometers, and VLF radio receivers as well as with measurements from the GOMOS/Envisat satellite instrument. For the first time, GOMOS was able to observe the SPE effects on odd nitrogen and ozone in the winter polar region. Ozone observations from GOMOS were validated against those from MIPAS/Envisat instrument, and a good agreement was found throughout the middle atmosphere. For the case of the SPE of October/November 2003, long-term ozone depletion was observed in the upper stratosphere. The depletion was further enhanced by the descent of odd nitrogen from the mesosphere inside the polar vortex, until the recovery occurred in late December. During the event, substantial diurnal variation of ozone depletion was seen in the mesosphere, caused mainly by the the strong diurnal cycle of the odd hydrogen species. In the lower ionosphere, SPEs increase the electron density which is very low in normal conditions. Therefore, SPEs make radar observations easier. In the case of the SPE of October, 1989, we studied the sunset transition of negative charge from electrons to ions, a long-standing problem. The observed phenomenon, which is controlled by the amount of solar radiation, was successfully explained by considering twilight changes in both the rate of photodetachment of negative ions and concentrations of minor neutral species. Changes in the magnetic field of the Earth control the extent of SPE-affected area. For the SPE of November 2001, the results indicated that for low and middle levels of geomagnetic disturbance the estimated cosmic radio noise absorption levels based on a magnetic field model are in a good agreement with ionospheric observations. For high levels of disturbance, the model overestimates the stretching of the geomagnetic field and the geographical extent of SPE-affected area. This work shows the importance of ionosphere-atmosphere interaction for SPE studies. By using both ionospheric and atmospheric observations, we have been able to cover for the most part the whole chain of SPE-triggered processes, from proton-induced ionisation to depletion of ozone.

Interatomic potentials for fusion reactor material simulations

Fusion energy is a clean and safe solution for the intricate question of how to produce non-polluting and sustainable energy for the constantly growing population. The fusion process does not result in any harmful waste or green-house gases, since small amounts of helium is the only bi-product that is produced when using the hydrogen isotopes deuterium and tritium as fuel. Moreover, deuterium is abundant in seawater and tritium can be bred from lithium, a common metal in the Earth's crust, rendering the fuel reservoirs practically bottomless. Due to its enormous mass, the Sun has been able to utilize fusion as its main energy source ever since it was born. But here on Earth, we must find other means to achieve the same. Inertial fusion involving powerful lasers and thermonuclear fusion employing extreme temperatures are examples of successful methods. However, these have yet to produce more energy than they consume. In thermonuclear fusion, the fuel is held inside a tokamak, which is a doughnut-shaped chamber with strong magnets wrapped around it. Once the fuel is heated up, it is controlled with the help of these magnets, since the required temperatures (over 100 million degrees C) will separate the electrons from the nuclei, forming a plasma. Once the fusion reactions occur, excess binding energy is released as energetic neutrons, which are absorbed in water in order to produce steam that runs turbines. Keeping the power losses from the plasma low, thus allowing for a high number of reactions, is a challenge. Another challenge is related to the reactor materials, since the confinement of the plasma particles is not perfect, resulting in particle bombardment of the reactor walls and structures. Material erosion and activation as well as plasma contamination are expected. Adding to this, the high energy neutrons will cause radiation damage in the materials, causing, for instance, swelling and embrittlement. In this thesis, the behaviour of a material situated in a fusion reactor was studied using molecular dynamics simulations. Simulations of processes in the next generation fusion reactor ITER include the reactor materials beryllium, carbon and tungsten as well as the plasma hydrogen isotopes. This means that interaction models, {\it i.e. interatomic potentials}, for this complicated quaternary system are needed. The task of finding such potentials is nonetheless nearly at its end, since models for the beryllium-carbon-hydrogen interactions were constructed in this thesis and as a continuation of that work, a beryllium-tungsten model is under development. These potentials are combinable with the earlier tungsten-carbon-hydrogen ones. The potentials were used to explain the chemical sputtering of beryllium due to deuterium plasma exposure. During experiments, a large fraction of the sputtered beryllium atoms were observed to be released as BeD molecules, and the simulations identified the swift chemical sputtering mechanism, previously not believed to be important in metals, as the underlying mechanism. Radiation damage in the reactor structural materials vanadium, iron and iron chromium, as well as in the wall material tungsten and the mixed alloy tungsten carbide, was also studied in this thesis. Interatomic potentials for vanadium, tungsten and iron were modified to be better suited for simulating collision cascades that are formed during particle irradiation, and the potential features affecting the resulting primary damage were identified. Including the often neglected electronic effects in the simulations was also shown to have an impact on the damage. With proper tuning of the electron-phonon interaction strength, experimentally measured quantities related to ion-beam mixing in iron could be reproduced. The damage in tungsten carbide alloys showed elemental asymmetry, as the major part of the damage consisted of carbon defects. On the other hand, modelling the damage in the iron chromium alloy, essentially representing steel, showed that small additions of chromium do not noticeably affect the primary damage in iron. Since a complete assessment of the response of a material in a future full-scale fusion reactor is not achievable using only experimental techniques, molecular dynamics simulations are of vital help. This thesis has not only provided insight into complicated reactor processes and improved current methods, but also offered tools for further simulations. It is therefore an important step towards making fusion energy more than a future goal.