Cancer incidence, mortality, and pregnancy outcome among women treated for cervical intraepithelial neoplasia

Cervical cancer develops through precursor lesions, i.e. cervical intraepithelialneoplasms (CIN). These can be detected and treated before progression to invasive cancer. The major risk factor for developing cervical cancer or CIN is persistent or recurrent infection with high-risk human papilloma virus (hrHPV). Other associated risk factors include low socioeconomic status, smoking, sexually transmitted infections, and high number of sexual partners, and these risk factors can predispose to some other cancers, excess mortality, and reproductive health complications as well. The aim was to study long-term cancer incidence, mortality, and reproductive health outcomes among women treated for CIN. Based on the results, we could evaluate the efficacy and safety of CIN treatment practices and estimate the role of the risk factors of CIN patients for cancer incidence, mortality, and reproductive health. We collected a cohort of 7 599 women treated for CIN at Helsinki University Central Hospital from 1974 to 2001. Information about their cancer incidence, cause of death, birth of children and other reproductive endpoints, and socio-economic status were gathered through registerlinkages to the Finnish Cancer Registry, Finnish Population Registry, and Statistics Finland. Depending on the endpoints in question, the women treated were compared to the general population, to themselves, or to an age- and municipality-matched reference cohort. Cervical cancer incidence was increased after treatment of CIN for at least 20 years, regardless of the grade of histology at treatment. Compared to all of the colposcopically guided methods, cold knife conization (CKC) was the least effective method of treatment in terms of later CIN 3 or cervical cancer incidence. In addition to cervical cancer, incidence of other HPV-related anogenital cancers was increased among those treated, as was the incidence of lung cancer and other smoking-related cancers. Mortality from cervical cancer among the women treated was not statistically significantly elevated, and after adjustment for socio-economic status, the hazard ratio (HR) was 1.0. In fact, the excess mortality among those treated was mainly due to increased mortality from other cancers, especially from lung cancer. In terms of post-treatment fertility, the CIN treatments seem to be safe: The women had more deliveries, and their incidence of pregnancy was similar before and after treatment. Incidence of extra-uterine pregnancies and induced abortions was elevated among the treated both before and after treatment. Thus this elevation did not occur because they were treated rather to a great extent was due to the other known risk factors these women had in excess, i.e. sexually transmitted infections. The purpose of any cancer preventive activity is to reduce cancer incidence and mortality. In Finland, cervical cancer is a rare disease and death from it even rarer, mostly due to the effective screening program. Despite this, the women treated are at increased risk for cancer; not just for cervical cancer. They must be followed up carefully and for a long period of time; general health education, especially cessation of smoking, is crucial in the management process, as well as interventions towards proper use of birth control such as condoms.

Individualized immunosuppression after renal transplantation in childhood

Pediatric renal transplantation (TX) has evolved greatly during the past few decades, and today TX is considered the standard care for children with end-stage renal disease. In Finland, 191 children had received renal transplants by October 2007, and 42% of them have already reached adulthood. Improvements in treatment of end-stage renal disease, surgical techniques, intensive care medicine, and in immunosuppressive therapy have paved the way to the current highly successful outcomes of pediatric transplantation. In children, the transplanted graft should last for decades, and normal growth and development should be guaranteed. These objectives set considerable requirements in optimizing and fine-tuning the post-operative therapy. Careful optimization of immunosuppressive therapy is crucial in protecting the graft against rejection, but also in protecting the patient against adverse effects of the medication. In the present study, the results of a retrospective investigation into individualized dosing of immunosuppresive medication, based on pharmacokinetic profiles, therapeutic drug monitoring, graft function and histology studies, and glucocorticoid biological activity determinations, are reported. Subgroups of a total of 178 patients, who received renal transplants in 1988 2006 were included in the study. The mean age at TX was 6.5 years, and approximately 26% of the patients were <2 years of age. The most common diagnosis leading to renal TX was congenital nephrosis of the Finnish type (NPHS1). Pediatric patients in Finland receive standard triple immunosuppression consisting of cyclosporine A (CsA), methylprednisolone (MP) and azathioprine (AZA) after renal TX. Optimal dosing of these agents is important to prevent rejections and preserve graft function in one hand, and to avoid the potentially serious adverse effects on the other hand. CsA has a narrow therapeutic window and individually variable pharmacokinetics. Therapeutic monitoring of CsA is, therefore, mandatory. Traditionally, CsA monitoring has been based on pre-dose trough levels (C0), but recent pharmacokinetic and clinical studies have revealed that the immunosuppressive effect may be related to diurnal CsA exposure and blood CsA concentration 0-4 hours after dosing. The two-hour post-dose concentration (C2) has proved a reliable surrogate marker of CsA exposure. Individual starting doses of CsA were analyzed in 65 patients. A recommended dose based on a pre-TX pharmacokinetic study was calculated for each patient by the pre-TX protocol. The predicted dose was clearly higher in the youngest children than in the older ones (22.9±10.4 and 10.5±5.1 mg/kg/d in patients <2 and >8 years of age, respectively). The actually administered oral doses of CsA were collected for three weeks after TX and compared to the pharmacokinetically predicted dose. After the TX, dosing of CsA was adjusted according to clinical parameters and blood CsA trough concentration. The pharmacokinetically predicted dose and patient age were the two significant parameters explaining post-TX doses of CsA. Accordingly, young children received significantly higher oral doses of CsA than the older ones. The correlation to the actually administered doses after TX was best in those patients, who had a predicted dose clearly higher or lower (> ±25%) than the average in their age-group. Due to the great individual variation in pharmacokinetics standardized dosing of CsA (based on body mass or surface area) may not be adequate. Pre-Tx profiles are helpful in determining suitable initial CsA doses. CsA monitoring based on trough and C2 concentrations was analyzed in 47 patients, who received renal transplants in 2001 2006. C0, C2 and experienced acute rejections were collected during the post-TX hospitalization, and also three months after TX when the first protocol core biopsy was obtained. The patients who remained rejection free had slightly higher C2 concentrations, especially very early after TX. However, after the first two weeks also the trough level was higher in the rejection-free patients than in those with acute rejections. Three months after TX the trough level was higher in patients with normal histology than in those with rejection changes in the routine biopsy. Monitoring of both the trough level and C2 may thus be warranted to guarantee sufficient peak concentration and baseline immunosuppression on one hand and to avoid over-exposure on the other hand. Controlling of rejection in the early months after transplantation is crucial as it may contribute to the development of long-term allograft nephropathy. Recently, it has become evident that immunoactivation fulfilling the histological criteria of acute rejection is possible in a well functioning graft with no clinical sings or laboratory perturbations. The influence of treatment of subclinical rejection, diagnosed in 3-month protocol biopsy, to graft function and histology 18 months after TX was analyzed in 22 patients and compared to 35 historical control patients. The incidence of subclinical rejection at three months was 43%, and the patients received a standard rejection treatment (a course of increased MP) and/or increased baseline immunosuppression, depending on the severity of rejection and graft function. Glomerular filtration rate (GFR) at 18 months was significantly better in the patients who were screened and treated for subclinical rejection in comparison to the historical patients (86.7±22.5 vs. 67.9±31.9 ml/min/1.73m2, respectively). The improvement was most remarkable in the youngest (<2 years) age group (94.1±11.0 vs. 67.9±26.8 ml/min/1.73m2). Histological findings of chronic allograft nephropathy were also more common in the historical patients in the 18-month protocol biopsy. All pediatric renal TX patients receive MP as a part of the baseline immunosuppression. Although the maintenance dose of MP is very low in the majority of the patients, the well-known steroid-related adverse affects are not uncommon. It has been shown in a previous study in Finnish pediatric TX patients that steroid exposure, measured as area under concentration-time curve (AUC), rather than the dose correlates with the adverse effects. In the present study, MP AUC was measured in sixteen stable maintenance patients, and a correlation with excess weight gain during 12 months after TX as well as with height deficit was found. A novel bioassay measuring the activation of glucocorticoid receptor dependent transcription cascade was also employed to assess the biological effect of MP. Glucocorticoid bioactivity was found to be related to the adverse effects, although the relationship was not as apparent as that with serum MP concentration. The findings in this study support individualized monitoring and adjustment of immunosuppression based on pharmacokinetics, graft function and histology. Pharmacokinetic profiles are helpful in estimating drug exposure and thus identifying the patients who might be at risk for excessive or insufficient immunosuppression. Individualized doses and monitoring of blood concentrations should definitely be employed with CsA, but possibly also with steroids. As an alternative to complete steroid withdrawal, individualized dosing based on drug exposure monitoring might help in avoiding the adverse effects. Early screening and treatment of subclinical immunoactivation is beneficial as it improves the prospects of good long-term graft function.

Detection of renal dysfunction during and after anaesthesia and surgery - evaluation of the influence of inorganic fluoride, ketorolac and clonidine

Drugs and surgical techniques may have harmful renal effects during the perioperative period. Traditional biomarkers are often insensitive to minor renal changes, but novel biomarkers may more accurately detect disturbances in glomerular and tubular function and integrity. The purpose of this study was first, to evaluate the renal effects of ketorolac and clonidine during inhalation anesthesia with sevoflurane and isoflurane, and secondly, to evaluate the effect of tobacco smoking on the production of inorganic fluoride (F-) following enflurane and sevoflurane anesthesia as well as to determine the effect of F- on renal function and cellular integrity in surgical patients. A total of 143 patients undergoing either conventional (n = 75) or endoscopic (n = 68) inpatient surgery were enrolled in four studies. The ketorolac and clonidine studies were prospective, randomized, placebo controlled and double-blinded, while the cigarette smoking studies were prospective cohort studies with two parallel groups. As a sign of proximal tubular deterioration, a similar transient increase in urine N-acetyl-beta-D-glucosaminidase/creatinine (U-NAG/crea) was noted in both the ketorolac group and in the controls (baseline vs. at two hours of anesthesia, p = 0.015) with a 3.3 minimum alveolar concentration hour sevoflurane anesthesia. Uncorrelated U-NAG increased above the maximum concentration measured from healthy volunteers (6.1 units/l) in 5/15 patients with ketorolac and in none of the controls (p = 0.042). As a sign of proximal tubular deterioration, U-glutathione transferase-alpha/crea (U-GST-alpha/crea) increased in both groups at two hours after anesthesia but a more significant increase was noted in the patients with ketorolac. U-GST-alpha/crea increased above the maximum ratio measured from healthy volunteers in 7/15 patients with ketorolac and in 3/15 controls. Clonidine diminished the activation of the renin-angiotensin aldosterone system during pneumoperitoneum; urine output was better preserved in the patients treated with clonidine (1/15 patients developed oliguria) than in the controls (8/15 developed oliguria (p=0.005)). Most patients with pneumoperitoneum and isoflurane anesthesia developed a transient proximal tubular deterioration, as U-NAG increased above 6.1 units/L in 11/15 patients with clonidine and in 7/15 controls. In the patients receiving clonidine treatment, the median of U-NAG/crea was higher than in the controls at 60 minutes of pneumoperitoneum (p = 0.01), suggesting that clonidine seems to worsen proximal tubular deterioration. Smoking induced the metabolism of enflurane, but the renal function remained intact in both the smokers and the non-smokers with enflurane anesthesia. On the contrary, smoking did not induce sevoflurane metabolism, but glomerular function decreased in 4/25 non-smokers and in 7/25 smokers with sevoflurane anesthesia. All five patients with S-F- ≥ 40 micromol/L, but only 6/45 with S-F- less than 40 micromol/L (p = 0.001), developed a S-tumor associated trypsin inhibitor concentration above 3 nmol/L as a sign of glomerular dysfunction. As a sign of proximal tubulus deterioration, U-beta 2-microglobulin increased in 2/5 patients with S-F- over 40 micromol/L compared to 2/45 patients with the highest S-F- less than 40 micromol/L (p = 0.005). To conclude, sevoflurane anesthesia may cause a transient proximal tubular deterioration which may be worsened by a co-administration of ketorolac. Clonidine premedication prevents the activation of the renin-angiotensin aldosterone system and preserves normal urine output, but may be harmful for proximal tubules during pneumoperitoneum. Smoking induces the metabolism of enflurane but not that of sevoflurane. Serum F- of 40 micromol/L or higher may induce glomerular dysfunction and proximal tubulus deterioration in patients with sevoflurane anesthesia. The novel renal biomarkers warrant further studies in order to establish reference values for surgical patients having inhalation anesthesia.

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.

Distal anterior cerebral artery aneurysms

Objective: Distal anterior cerebral artery (DACA) aneurysms represent about 6% of all intracranial aneurysms. So far, only small series on treatment of these aneurysms have been published. Our aim is to evaluate the anatomic features, microneurosurgical techniques, treatment results, and long-term outcome in patients treated for DACA aneurysms. Patients and methods: We analyzed the clinical and radiological data on 517 consecutive patients diagnosed with DACA aneurysm at two neurosurgical centers serving solely the Southern (Helsinki) and Eastern (Kuopio) Finland in 1936–2007, and used a defined subgroup of the whole study population in each part of the study. Detailed anatomic analysis was performed in 101 consecutive patients from 1998 to 2007. Treatment results were analyzed in 427 patients treated between 1980 to 2005, the era of CT imaging and microneurosurgery. Long-term treatment outcome of ruptured DACA aneurysm(s) was evaluated in 280 patients with a median follow-up of 10 years; no patients were lost to follow-up. Results: DACA aneurysms, found most often (83%) at the A3 segment of the anterior cerebral artery (ACA), were smaller (median 6 mm vs. 8 mm), more frequently associated with multiple aneurysms (35% vs. 18%), and presented more often with intracerebral hematomas (ICHs) (53% vs. 26%) than ruptured aneurysms in general. They were associated with anomalies of the ACA in 23% of the patients. Microsurgical treatment showed similar complication rates (treatment morbidity 15%, treatment mortality 0.4%) as for other ruptured aneurysms. At one year after subarachnoid hemorrhage (SAH), DACA aneurysms had equally favorable outcome (GOS≥4) as other ruptured aneurysms (74% vs. 69%) but their mortality was lower (13% vs. 24%). Factors predicting unfavorable outcome for ruptured DACA aneurysms were advanced age, Hunt&Hess≥3, rebleeding before treatment, ICH, intraventricular hemorrhage, and severe preoperative hydrocephalus. The cumulative relative survival ratio showed 16% excess mortality in patients with ruptured DACA aneurysm during the first three years after SAH compared to the matched general population. From the fourth year onwards, there was no excess mortality during the follow-up. There were four episodes of recurrent SAH, only one due to treated DACA aneurysm, with a 10-year cumulative risk of 1.4%. Conclusions: The special neurovascular features and frequent association with anterior cerebral artery anomalies must be taken into account when planning occlusive treatment of DACA aneurysms. Clipping of DACA aneurysms provides a long-lasting result, with very small rates of rebleeding. After surviving three years from rupture of DACA aneurysm, the long-term survival of these patients becomes similar to that of the matched general population.

Matrix proteinases in lung injury in the preterm infant

During inflammation, excess production and release of matrix proteinases, including matrix metalloproteinases (MMPs) and serine proteinases, may result in dysregulated extracellular proteolysis leading to development of tissue damage. Pulmonary inflammation may play an important role in the pathogenesis of lung injury in the preterm infant. The aims of this study were to evaluate involvement of MMPs and serine proteinase trypsin in acute and chronic lung injury in preterm infants and to study the role of these enzymes in acute lung injury by means of an animal model of hyperoxic lung injury. Molecular forms and levels of MMP-2, -8, and -9, and their specific inhibitor, tissue inhibitor of metalloproteinases (TIMP)-2, as well as trypsin were studied in tracheal aspirate fluid (TAF) samples collected from preterm infants with respiratory distress. Expression and distribution of trypsin-2 and proteinase-activated receptor 2 (PAR2) was examined in autopsy lung specimens from fetuses, from preterm infants with respiratory distress syndrome (RDS) or bronchopulmonary dysplasia (BPD), and from newborn infants without lung injury. We detected higher MMP-8 and trypsin-2 and lower TIMP-2 in TAF from preterm infants with more severe acute respiratory distress. Infants subsequently developing BPD had higher levels of MMP-8 and trypsin-2 early postnatally than did those who survived without this chronic lung injury. Immunohistochemically, trypsin-2 was mainly detectable in bronchial epithelium, but also in alveolar epithelium, and its expression was strongest in prolonged RDS. Since trypsin-2 is potent activator of PAR2, a G-protein coupled receptor involved in inflammation, we studied PAR2 expression in the lung. PAR2 co-localized with trypsin-2 in bronchoalveolar epithelium and its expression was significantly higher in bronchoalveolar epithelium in preterm infants with prolonged RDS than in newborn controls. In the experimental study, rats were exposed to >95% oxygen for 24, 48, and 60 hours, or room air. At 48 hours of hyperoxia, MMP-8 and trypsin levels sharply increased in bronchoalveolar lavage fluid, and expression of trypsin appeared in alveolar epithelium, and MMP-8 predominantly in macrophages. In conclusion, high pulmonary MMP-8 and trypsin-2 early postnatally are associated with severity of acute lung injury and subsequent development of BPD in preterm infants. In the injured preterm lung, trypsin-2 co-localizes with PAR2 in bronchoalveolar epithelium, suggesting that PAR2 activated by high levels of trypsin-2 is involved in lung inflammation associated with development of BPD. Marked increase in MMP-8 and trypsin early in the course of experimental hyperoxic lung injury suggests that these enzymes play a role in the pathogenesis of acute lung injury. Further exploration of the roles of trypsin and MMP-8 in lung injury may offer new targets for therapeutic intervention.

Thrombin regulation in newborn infants

The coagulation system of newborn infants differs markedly from that of older children and adults. The activities of most coagulation factors and anticoagulants are low, leading to altered regulation in the formation of the key enzyme, thrombin. Timely and adequate generation of thrombin is essential, as thrombin activates platelets and many coagulation factors, cleaves fibrinogen into fibrin and activates the antithrombotic and anti-inflammatory protein C pathway. On the other hand, excess thrombin may promote thrombotic complications and exacerbate harmful inflammatory reactions. Despite the characteristic features, the newborn coagulation system can be considered physiological, since healthy newborns rarely show haemorrhagic or thrombotic complications. Sick newborns, however, often encounter clinical situations that challenge their coagulation system. The aim of this study was to clarify the behaviour of the neonatal coagulation system in selected clinical situations, with a special emphasis on the generation of thrombin. Thrombin was measured by in vivo thrombin generation markers and by thrombin generation potential in vitro. The patient groups included sick newborns undergoing intensive care and receiving fresh-frozen plasma (FFP), requiring exchange transfusions (ET) or presenting with a congenital heart defect requiring open heart surgery. Additionally, healthy newborns with inherited heterozygous factor V Leiden (FVL) mutation were studied. Thrombin generation potential was also analysed in cord plasma of healthy infants and in adults. Healthy as well as sick newborn infants showed lower total thrombin generation potential in vitro but faster initiation of thrombin generation than adults. These findings were qualitatively similar when plasma was supplemented with platelets. Platelets, however, significantly altered the effect of the major anticoagulant, activated protein C (APC), on thrombin generation potential. In accordance with previous studies, thrombin generation in healthy newborn platelet-poor plasma was resistant to the anticoagulant effects of APC, but when the plasma was supplemented with platelets APC attenuated thrombin generation significantly more in newborns than in adults. In vivo generation of thrombin was elevated in nearly all of the sick newborn infants. The low-volume FFP transfusion as opposed to the change from neonatal to adult blood in ET exerted markedly different effects on neonatal thrombin generation. FFP reduced the in vivo generation of thrombin in those newborns with the highest pretransfusional thrombin generation, thus acting as an anticoagulant agent. In those infants with lower pretransfusional thrombin generation, the effect of FFP on thrombin generation was fairly neutral. On the other hand, the combination of red blood cells and FFP, used to perform ET, significantly increased the in vivo thrombin formation and shifted the balance in the newborn coagulation system to the procoagulant direction. Cardiopulmonary bypass (CPB) also significantly increased the in vivo thrombin generation, but the thrombin generation profile during CPB differed from that previously observed in adults. Escalation of thrombin at early reperfusion was not observed in newborns; in adults, its occurrence is associated with postoperative myocardial damage. Finally, in healthy newborns with FVL heterozygosity, faster initiation of thrombin generation was observed compared with controls. Interestingly, FV level was lower in FVL-heterozygous infants, possibly to counteract the procoagulant effects induced by FVL. In conclusion, unique features regarding thrombin regulation in newborn infants were observed. These features included a novel platelet effect on the regulation of the protein C pathway. The clinical challenges mainly seemed to shift the balance in the coagulation system of newborns to the procoagulant direction. Blood component transfusions markedly affected coagulation in a manner specific to the product but that could also be altered by the clinical situation. Overall, the results highlight the need for understanding developmental haemostasis for both diagnostic and therapeutic purposes.

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.

Two views on interstellar dust: near-infrared scattering and polarized thermal dust emission

Interstellar clouds are not featureless, but show quite complex internal structures of filaments and clumps when observed with high enough resolution. These structures have been generated by 1) turbulent motions driven mainly by supernovae, 2) magnetic fields working on the ions and, through neutral-ion collisions, on neutral gas as well, and 3) self-gravity pulling a dense clump together to form a new star. The study of the cloud structure gives us information on the relative importance of each of these mechanisms, and helps us to gain a better understanding of the details of the star formation process. Interstellar dust is often used as a tracer for the interstellar gas which forms the bulk of the interstellar matter. Some of the methods that are used to derive the column density are summarized in this thesis. A new method, which uses the scattered light to map the column density in large fields with high spatial resolution, is introduced. This thesis also takes a look at the grain alignment with respect to the magnetic fields. The aligned grains give rise to the polarization of starlight and dust emission, thus revealing the magnetic field. The alignment mechanisms have been debated for the last half century. The strongest candidate at present is the radiative torques mechanism. In the first four papers included in this thesis, the scattered light method of column density estimation is formulated, tested in simulations, and finally used to obtain a column density map from observations. They demonstrate that the scattered light method is a very useful and reliable tool in column density estimation, and is able to provide higher resolution than the near-infrared color excess method. These two methods are complementary. The derived column density maps are also used to gain information on the dust emissivity within the observed cloud. The two final papers present simulations of polarized thermal dust emission assuming that the alignment happens by the radiative torques mechanism. We show that the radiative torques can explain the observed decline of the polarization degree towards dense cores. Furthermore, the results indicate that the dense cores themselves might not contribute significantly to the polarized signal, and hence one needs to be careful when interpreting the observations and deriving the magnetic field.

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.

Determinants of institutional care at older ages in Finland

Väitöskirjassa selvitettiin ikäihmisten laitoshoitoon siirtymisen todennäköisyyttä ja sen taustoja kansainvälisesti ainutlaatuisen rekisteriaineiston avulla. Selvitettäviä asioita olivat eri sairauksien, sosioekonomisten tekijöiden, puolison olemassaolon ja leskeksi jäämisen yhteys laitoshoitoon siirtymiseen yli 65-vuotiailla suomalaisilla. Tutkimuksessa havaittiin, että dementia, Parkinsonin tauti, aivohalvaus, masennusoireet ja muut mielenterveysongelmat, lonkkamurtuma sekä diabetes lisäsivät ikäihmisten todennäköisyyttä siirtyä laitoshoitoon yli 50 prosentilla, kun muut sairaudet ja sosiodemografiset tekijät oli otettu huomioon. Korkeat tulot vähensivät laitoshoidon todennäköisyyttä, kun taas puutteellinen asuminen (ilman peseytymistiloja tai keskus- tai sähkölämmitystä) sekä erittäin puutteellinen asuminen (ilman lämmintä vettä, vesijohtoa, viemäriä tai vesivessaa) lisäsivät todennäkösyyttä, kun muut sosiodemografiset tekijät, sairaudet ja asuinalue oli huomioitu. Kerrostalon hissittömyys ei ollut yhteydessä laitoshoidon todennäköisyyteen. Todennäköisyys siirtyä laitoshoitoon oli jostain syystä korkeampaa niillä ikäihmisillä, jotka asuivat vuokralla ja matalampaa omakotitalossa asuvilla ja niillä, joilla oli auto. Puolison olemassaolo vähensi ja leskeksi jääminen lisäsi laitoshoidon todennäköisyyttä huomattavasti. Todennäköisyys oli erityisen suuri, yli kolminkertainen, kun puolison kuolemasta oli kulunut enintään kuukausi verrattuna niihin, joiden puoliso oli elossa. Todennäköisyys laski, kun puolison kuolemasta kului aikaa. Miesten ja naisten tulokset olivat samansuuntaisia. Korkeat tulot tai koulutus eivät suojanneet riskiltä joutua laitoshoitoon puolison kuoltua. Puolison kuolema näyttää lisäävän hoidon tarvetta, kun kotona ei ole enää puolisoa tukemassa ja huolehtimassa kodin askareista. Laitoshoidon tarve vähenee, jos ja kun lesket ajan kuluessa oppivat elämään yksin. Toisaalta tutkimustulokset saattavat viitata myös siihen, että kaikkein huonokuntoisimmat lesket, jotka eivät pärjää yksin asuessaan, siirtyvät laitoshoitoon hyvin nopeasti puolison kuoltua. Tutkimuksessa oli mukana yhteensä yli 280 000 yli 65-vuotiasta henkilöä, joiden pitkäaikaiseen laitoshoitoon siirtymistä seurattiin tammikuusta 1998 syyskuuhun 2003. Laitoshoidoksi määriteltiin terveyskeskuksissa, sairaaloissa ja vanhainkodeissa tai vastaavissa yksiköissä tapahtuva pitkäaikainen hoito, joka kesti yli 90 vuorokautta tai oli vahvistettu pitkäaikaishoidon päätöksellä. Tutkimuksessa käytetty aineisto koottiin väestörekistereistä, sosiaali- ja terveydenhuollon rekistereistä ja lääkerekistereistä.

Not in all Walks of Life? : Social Differences in Suicide Mortality

In Finland, the suicide mortality trend has been decreasing during the last decade and a half, yet suicide was the fourth most common cause of death among both Finnish men and women aged 15 64 years in 2006. However, suicide does not occur equally among population sub-groups. Two notable social factors that position people at different risk of suicide are socioeconomic and employment status: those with low education, employed in manual occupations, having low income and those who are unemployed have been found to have an elevated suicide risk. The purpose of this study was to provide a systematic analysis of these social differences in suicide mortality in Finland. Besides studying socioeconomic trends and differences in suicide according to age and sex, different indicators for socioeconomic status were used simultaneously, taking account of their pathways and mutual associations while also paying attention to confounding and mediatory effects of living arrangements and employment status. Register data obtained from Statistics Finland were used in this study. In some analyses suicides were divided into two groups according to contributory causes of death: the first group consisted of suicide deaths that had alcohol intoxication as one of the contributory causes, and the other group is comprised of all other suicide deaths. Methods included Poisson and Cox regression models. Despite the decrease in suicide mortality trend, social differences still exist. Low occupation-based social class proved to be an important determinant of suicide risk among both men and women, but the strong independent effect of education on alcohol-associated suicide indicates that the roots of these differences are probably established in early adulthood when educational qualifications are obtained and health-behavioural patterns set. High relative suicide mortality among the unemployed during times of economic boom suggests that selective processes may be responsible for some of the employment status differences in suicide. However, long-term unemployment seems to have causal effects on suicide, which, especially among men, partly stem from low income. In conclusion, the results in this study suggest that education, occupation-based social class and employment status have causal effects on suicide risk, but to some extent selection into low education and unemployment are also involved in the explanations for excess suicide mortality among the socially deprived. It is also conceivable that alcohol use is to some extent behind social differences in suicide. In addition to those with low education, manual workers and the unemployed, young people, whose health-related behaviour is still to be adopted, would most probably benefit from suicide prevention programmes.

Studies on Binary Time Series Models with Applications to Empirical Macroeconomics and Finance

This thesis studies binary time series models and their applications in empirical macroeconomics and finance. In addition to previously suggested models, new dynamic extensions are proposed to the static probit model commonly used in the previous literature. In particular, we are interested in probit models with an autoregressive model structure. In Chapter 2, the main objective is to compare the predictive performance of the static and dynamic probit models in forecasting the U.S. and German business cycle recession periods. Financial variables, such as interest rates and stock market returns, are used as predictive variables. The empirical results suggest that the recession periods are predictable and dynamic probit models, especially models with the autoregressive structure, outperform the static model. Chapter 3 proposes a Lagrange Multiplier (LM) test for the usefulness of the autoregressive structure of the probit model. The finite sample properties of the LM test are considered with simulation experiments. Results indicate that the two alternative LM test statistics have reasonable size and power in large samples. In small samples, a parametric bootstrap method is suggested to obtain approximately correct size. In Chapter 4, the predictive power of dynamic probit models in predicting the direction of stock market returns are examined. The novel idea is to use recession forecast (see Chapter 2) as a predictor of the stock return sign. The evidence suggests that the signs of the U.S. excess stock returns over the risk-free return are predictable both in and out of sample. The new "error correction" probit model yields the best forecasts and it also outperforms other predictive models, such as ARMAX models, in terms of statistical and economic goodness-of-fit measures. Chapter 5 generalizes the analysis of univariate models considered in Chapters 2 4 to the case of a bivariate model. A new bivariate autoregressive probit model is applied to predict the current state of the U.S. business cycle and growth rate cycle periods. Evidence of predictability of both cycle indicators is obtained and the bivariate model is found to outperform the univariate models in terms of predictive power.

Spectroscopy of tissue triglyceride composition : In vitro and in vivo studies

Lipid analysis is commonly performed by gas chromatography (GC) in laboratory conditions. Spectroscopic techniques, however, are non-destructive and can be implemented noninvasively in vivo. Excess fat (triglycerides) in visceral adipose tissue and liver is known predispose to metabolic abnormalities, collectively known as the metabolic syndrome. Insulin resistance is the likely cause with diets high in saturated fat known to impair insulin sensitivity. Tissue triglyceride composition has been used as marker of dietary intake but it can also be influenced by tissue specific handling of fatty acids. Recent studies have shown that adipocyte insulin sensitivity correlates positively with their saturated fat content, contradicting the common view of dietary effects. A better understanding of factors affecting tissue triglyceride composition is needed to provide further insights into tissue function in lipid metabolism. In this thesis two spectroscopic techniques were developed for in vitro and in vivo analysis of tissue triglyceride composition. In vitro studies (Study I) used infrared spectroscopy (FTIR), a fast and cost effective analytical technique well suited for multivariate analysis. Infrared spectra are characterized by peak overlap leading to poorly resolved absorbances and limited analytical performance. In vivo studies (Studies II, III and IV) used proton magnetic resonance spectroscopy (1H-MRS), an established non-invasive clinical method for measuring metabolites in vivo. 1H-MRS has been limited in its ability to analyze triglyceride composition due to poorly resolved resonances. Using an attenuated total reflection accessory, we were able to obtain pure triglyceride infrared spectra from adipose tissue biopsies. Using multivariate curve resolution (MCR), we were able to resolve the overlapping double bond absorbances of monounsaturated fat and polyunsaturated fat. MCR also resolved the isolated trans double bond and conjugated linoleic acids from an overlapping background absorbance. Using oil phantoms to study the effects of different fatty acid compositions on the echo time behaviour of triglycerides, it was concluded that the use of long echo times improved peak separation with T2 weighting having a negligible impact. It was also discovered that the echo time behaviour of the methyl resonance of omega-3 fats differed from other fats due to characteristic J-coupling. This novel insight could be used to detect omega-3 fats in human adipose tissue in vivo at very long echo times (TE = 470 and 540 ms). A comparison of 1H-MRS of adipose tissue in vivo and GC of adipose tissue biopsies in humans showed that long TE spectra resulted in improved peak fitting and better correlations with GC data. The study also showed that calculation of fatty acid fractions from 1H-MRS data is unreliable and should not be used. Omega-3 fatty acid content derived from long TE in vivo spectra (TE = 540 ms) correlated with total omega-3 fatty acid concentration measured by GC. The long TE protocol used for adipose tissue studies was subsequently extended to the analysis of liver fat composition. Respiratory triggering and long TE resulted in spectra with the olefinic and tissue water resonances resolved. Conversion of the derived unsaturation to double bond content per fatty acid showed that the results were in accordance with previously published gas chromatography data on liver fat composition. In patients with metabolic syndrome, liver fat was found to be more saturated than subcutaneous or visceral adipose tissue. The higher saturation observed in liver fat may be a result of a higher rate of de-novo-lipogenesis in liver than in adipose tissue. This thesis has introduced the first non-invasive method for determining adipose tissue omega-3 fatty acid content in humans in vivo. The methods introduced here have also shown that liver fat is more saturated than adipose tissue fat.

Combination of Tevatron Searches for the Standard Model Higgs Boson in the W+W- Decay Mode

We combine searches by the CDF and D0 collaborations for a Higgs boson decaying to W+W-. The data correspond to an integrated total luminosity of 4.8 (CDF) and 5.4 (D0) fb-1 of p-pbar collisions at sqrt{s}=1.96 TeV at the Fermilab Tevatron collider. No excess is observed above background expectation, and resulting limits on Higgs boson production exclude a standard-model Higgs boson in the mass range 162-166 GeV at the 95% C.L.