Early life determinants of atopy : A 20-year prospective follow-up study on unselected, healthy newborns

Atopy-related allergic diseases, i.e. allergic rhinoconjunctivitis, atopic dermatitis and asthma, have increased in frequency in the industrialized countries. In order to reverse this trend, effective preventive strategies need to be developed. This requires a better understanding of the early-life events leading to the expression of the atopic phenotype. The present study has aimed at defining early-life factors and markers associated with the subsequent development of allergic diseases in a cohort of 200 healthy, unselected Finnish newborns prospectively followed up from birth to age 20 years. Their mothers were encouraged to start and maintain exclusive breastfeeding as long as it was nutritionally sufficient for the infant. Consequently, all the infants received some duration of exclusive breastfeeding, 58% of the infants were on exclusive breastfeeding for the first 6 months of life, and 18% received this feeding at least for the first 9 months. Of the infants, 42% had a family history of allergy. After the first year of follow-up, the children were re-assessed at ages 5, 11 and 20 years with clinical examination, skin prick testing, and parental and personal interviews. Exclusive breastfeeding for over 9 months was associated with atopic dermatitis and symptoms of food hypersensitivity at age 5 years, and with symptoms of food hypersensitivity at age 11 years in the children with a familial allergy. Subjects with allergic symptoms or a positive skin prick test in childhood or adolescence had lower retinol concentrations during their infancy and childhood than others. An elevated cord serum immunoglobulin E concentration predicted subsequent atopic manifestations though with modest sensitivity. Children and adolescents with allergic symptoms, skin prick test positivity and an elevated IgE had lower total cholesterol levels in infancy and childhood than the nonatopic subjects. In conclusion, prolonging strictly exclusive breastfeeding for over 9 months of age was not of help in prevention of allergic symptoms; instead, it was associated with increased atopic dermatitis and food hypersensitivity symptoms in childhood. Due to the modest sensitivity, cord serum IgE is not an effective screening method for atopic predisposition in the general population. Retinol and cholesterol concentrations in infancy were inversely associated with the subsequent development of allergic symptoms. Based on these findings, it is proposed that there may be differences in the inborn regulation of retinol and cholesterol levels in children with and without a genetic susceptibility to atopy, and these may play a role in the development of atopic sensitization and allergic diseases.

Aritmetiikasta algebraan : Muutoksia osaamisessa peruskoulun päättöluokalla 20 vuoden aikana

From Arithmetic to Algebra. Changes in the skills in comprehensive school over 20 years. In recent decades we have emphasized the understanding of calculation in mathematics teaching. Many studies have found that better understanding helps to apply skills in new conditions and that the ability to think on an abstract level increases the transfer to new contexts. In my research I take into consideration competence as a matrix where content is in a horizontal line and levels of thinking are in a vertical line. The know-how is intellectual and strategic flexibility and understanding. The resources and limitations of memory have their effects on learning in different ways in different phases. Therefore both flexible conceptual thinking and automatization must be considered in learning. The research questions that I examine are what kind of changes have occurred in mathematical skills in comprehensive school over the last 20 years and what kind of conceptual thinking is demonstrated by students in this decade. The study consists of two parts. The first part is a statistical analysis of the mathematical skills and their changes over the last 20 years in comprehensive school. In the test the pupils did not use calculators. The second part is a qualitative analysis of the conceptual thinking of pupils in comprehensive school in this decade. The study shows significant differences in algebra and in some parts of arithmetic. The largest differences were detected in the calculation skills of fractions. In the 1980s two out of three pupils were able to complete tasks with fractions, but in the 2000s only one out of three pupils were able to do the same tasks. Also remarkable is that out of the students who could complete the tasks with fractions, only one out of three pupils was on the conceptual level in his/her thinking. This means that about 10% of pupils are able to understand the algebraic expression, which has the same isomorphic structure as the arithmetical expression. This finding is important because the ability to think innovatively is created when learning the basic concepts. Keywords: arithmetic, algebra, competence

Pharmacogenetic Variation at CYP2D6, CYP2C9, and CYP2C19: Population Genetic and Forensic Aspects

Pharmacogenetics deals with genetically determined variation in drug response. In this context, three phase I drug-metabolizing enzymes, CYP2D6, CYP2C9, and CYP2C19, have a central role, affecting the metabolism of about 20-30% of clinically used drugs. Since genes coding for these enzymes in human populations exhibit high genetic polymorphism, they are of major pharmacogenetic importance. The aims of this study were to develop new genotyping methods for CYP2D6, CYP2C9, and CYP2C19 that would cover the most important genetic variants altering the enzyme activity, and, for the first time, to describe the distribution of genetic variation at these loci on global and microgeographic scales. In addition, pharmacogenetics was applied to a postmortem forensic setting to elucidate the role of genetic variation in drug intoxications, focusing mainly on cases related to tricyclic antidepressants, which are commonly involved in fatal drug poisonings in Finland. Genetic variability data were obtained by genotyping new population samples by the methods developed based on PCR and multiplex single-nucleotide primer extension reaction, as well as by collecting data from the literature. Data consisted of 138, 129, and 146 population samples for CYP2D6, CYP2C9, and CYP2C19, respectively. In addition, over 200 postmortem forensic cases were examined with respect to drug and metabolite concentrations and genotypic variation at CYP2D6 and CYP2C19. The distribution of genetic variation within and among human populations was analyzed by descriptive statistics and variance analysis and by correlating the genetic and geographic distances using Mantel tests and spatial autocorrelation. The correlation between phenotypic and genotypic variation in drug metabolism observed in postmortem cases was also analyzed statistically. The genotyping methods developed proved to be informative, technically feasible, and cost-effective. Detailed molecular analysis of CYP2D6 genetic variation in a global survey of human populations revealed that the pattern of variation was similar to those of neutral genomic markers. Most of the CYP2D6 diversity was observed within populations, and the spatial pattern of variation was best described as clinal. On the other hand, genetic variants of CYP2D6, CYP2C9, and CYP2C19 associated with altered enzymatic activity could reach extremely high frequencies in certain geographic regions. Pharmacogenetic variation may also be significantly affected by population-specific demographic histories, as seen within the Finnish population. When pharmacogenetics was applied to a postmortem forensic setting, a correlation between amitriptyline metabolic ratios and genetic variation at CYP2D6 and CYP2C19 was observed in the sample material, even in the presence of confounding factors typical for these cases. In addition, a case of doxepin-related fatal poisoning was shown to be associated with a genetic defect at CYP2D6. Each of the genes studied showed a distinct variation pattern in human populations and high frequencies of altered activity variants, which may reflect the neutral evolution and/or selective pressures caused by dietary or environmental exposure. The results are relevant also from the clinical point of view since the genetic variation at CYP2D6, CYP2C9, and CYP2C19 already has a range of clinical applications, e.g. in cancer treatment and oral anticoagulation therapy. This study revealed that pharmacogenetics may also contribute valuable information to the medicolegal investigation of sudden, unexpected deaths.

Effects of dietary phosphorus and calcium-to-phosphorus ratio on calcium and bone metabolism in healthy 20- to 43-year-old Finnish women

Dietary habits have changed during the past decades towards an increasing consumption of processed foods, which has notably increased not only total dietary phosphorus (P) intake, but also intake of P from phosphate additives. While the intake of calcium (Ca) in many Western countries remains below recommended levels (800 mg/d), the usual daily P intake in a typical Western diet exceeds by 2- to 3-fold the dietary guidelines (600 mg/d). The effects of high P intake in healthy humans have been investigated seldom. In this thesis healthy 20- to 43-year-old women were studied. In the first controlled study (n = 14), we examined the effects of P doses, and in a cross-sectional study (n = 147) the associations of habitual P intakes with Ca and bone metabolism. In this same cross-sectional study, we also investigated whether differences exist between dietary P originating from natural P sources and phosphate additives. The second controlled study (n = 12) investigated whether by increasing the Ca intake, the effects of a high P intake could be reduced. The associations of habitual dietary calcium-to-phosphorus ratios (Ca:P ratio) with Ca and bone metabolism were determined in a cross-sectional study design (n = 147). In the controlled study, the oral intake of P doses (495, 745, 1245 and 1995 mg/d) with a low Ca intake (250 mg/d) increased serum parathyroid hormone (S-PTH) concentration in a dose-dependent manner. In addition, the highest P dose decreased serum ionized calcium (S-iCa) concentration and bone formation and increased bone resorption. In the second controlled study with a dietary P intake of 1850 mg/d, by increasing the Ca intake from 480 mg/d to 1080 mg/d and then to 1680 mg/d, the S-PTH concentration decreased, the S-iCa concentration increased and bone resorption decreased dose-dependently. However, not even the highest Ca intake could counteract the effect of high dietary P on bone formation, as indicated by unchanged bone formation activity. In the cross-sectional studies, a higher habitual dietary P intake (>1650 mg/d) was associated with lower S-iCa and higher S-PTH concentrations. The consumption of phosphate additive-containing foods was associated with a higher S-PTH concentration. Moreover, habitual low dietary Ca:P ratios (≤0.50, molar ratio) were associated with higher S-PTH concentrations and 24-h urinary Ca excretions, suggesting that low dietary Ca:P ratios may interfere with homeostasis of Ca metabolism and increase bone resorption. In summary, excessive dietary P intake in healthy Finnish women seems to be detrimental to Ca and bone metabolism, especially when dietary Ca intake is low. The results indicate that by increasing dietary Ca intake to the recommended level, the negative effects of high P intake could be diminished, but not totally prevented. These findings imply that phosphate additives may be more harmful than natural P. Thus, reduction of an excessively high dietary P intake is also beneficial for healthy individuals.

Keittiömaailman matkassa 20 vuotta : Tutkimus erään keittiökalustevalmistajan johtavan markkina-aseman rakentamisesta ja säilyttämisestä

A View into the World of Kitchen: Development and retention of a leading position in the market of kitchen interiors - a case study of 20 years. This study focuses on the development of a kitchen interiors company, presently called Novart Inc., into the leading company of the industry from 1980´s to the present. The objective of the study is to describe the effects of strategic choices, the decisions of the management and the owner´s direction and control to the build up and the retaining of the leading position in the market. From theory point of view, strategic choices refer to com-pany purchases as corporate-level strategies, and business and marketing strategies. The empirical research was carried out in two phases and it is based on various company documents and records, and on the intensive interviews of seven key executives in the company. An abductive research design was utilized. The company gained the leading position in the kitchen market in Finland by company purchases, and the company has been able to retain the position. Firstly the goal was to expand to retail market and, secondly, the company has maintained the balance of supply and demand by closing the purchased production units when needed. The simultaneous use of these two strategic goals is a kind of a new observation, and the strategy may be suitable only for market leaders. During the latter part of the research period the strategy of com-pany purchases has been abandoned and the leading position in the market has been main-tained by developing systematically business and marketing capability. In the business and marketing strategies the distribution channels and the brands have been emphasized. During the research period the company has almost totally abandoned the long distribution channels and started to use its own channels built and named after the main brands. These are A la Carte, Parma and Petra. At the moment, in the beginning of the 21st century, a new distribution channel, the concept of the Kitchen World, is being built in addition to the channels mentioned above. The management´s decision making and the implementation the decisions have been well-considered. The executives emphasized the valuing of the importance of the decisions dif-ferently except the two decisions named the most important ones, i.e., the decisions to start own production of the raw material and to concentrate the business only to one company. The executive staff has also succeeded in managing crisis and threats of bankruptcy, and the company has been managed profitable. During all the four terms of ownership: Puolimatka Corporation, the Hankkija/Novera Corporation, the ownership period of the "bank", and the Nobia Corporate the ownership direction and control has been somewhat different. All the owners have paid attention to economic issues. The direction of cash flows and investments was at its strongest during the Hankkija/Novera term. For the last owner Nobia the production and marketing of the kitchen interiors has been the core business, which thus has strengthened the business and marketing capabilities of the target company of this research. A common denominator during all the four terms of ownership has been owners' trust gained by the professional skills of the management of the target company. This has lead to greater independence of the management of the company and less owners´ direction. Keywords: leading position, marketing strategy, management decisions, acquisition, corporate governance

Jeremia 20:7-13 psykoanalyysissa : Nimettömän valituslaulun syntyprosessi tekstin objektimielikuvien muutosten valossa

Tämän pro gradu -työn tarkoituksena on selvittää tekstin Jer 20:7-13 jumalakuvaa ja muita ”tekstin puhujan” ilmaisemia vuorovaikutussuhteita ja vaihtelevia tunteita. On kuitenkin epäselvää, missä määrin Jeremian kirja tai sen yksittäiset jaksot kuvaavat profeetan persoonaa ja historiallista taustaa. Tekstit voivat kuvata myös muita myöhempiä tilanteita ja asenteita. Tämän tutkimuksen pääasiallinen eksegeettinen metodi on syvyyspsykologinen. Se saattaa pystyä kertomaan jotakin siitä, miten tutkittava teksti peilaa menneisyyden kokemuksellisia kaavoja. Samaan tapaan kuten psykohistoriassa, tutkimus ei yritä tutkia, tulkita tai rekonstruoida tradition tai historian Jeremiaa. Syvyyspsykologinen eksegeesi on tunnistettu jo aiemmin, mutta suomalaisessa tutkimuksessa sitä ei vielä ole sovellettu yksittäisiin teksteihin. Tämän tutkimuksen tutkimusasetelma avaa tekstin sisäisiä ja vaihtelevia vuorovaikutussuhteita eli objektisuhteita. Tutkimus nimittää tätä vuorovaikutussuhteiden analyysiä objektisuhdeanalyysiksi. Se perustuu teologian tohtori, psykoanalyytikko Matti Hyrckin psykoanalyyttiseen suhteessaolon perusmielikuvien teoriaan (SPT), jonka hän esittelee väitöskirjassaan Mielen kuvat Jumalasta (1995). Tekstin Jahve-kuvat on nähtävä objektirepresentaatioina. Nämä vahvasti värittyneet representaatiot ja kuvat kertovat enemmän kokijasta itsestään kuin niistä objekteista, joiden kuviksi ne ovat syntyneet. Käsitys objektien sisäsyntyisyydestä mahdollistaa Hyrckillä objektisuhteiden systematisoinnin ja SPT:n luomisen. Siten emotionaaliset silmälasit on tämän tutkimuksen tekijän mielestä mahdollista valjastaa myös tutkijan käyttöön. Tutkimuksen laaja näkökulmia hakeva teoriaosuus varmistaa tämän. Hermeneuttinen ”kolmen maailman malli” on lukijakeskeisyyteen ja kulttuurihyppyyn arvokas työväline. Jeremian kirja sisältää useita osin runomuotoisia valituksia, joista tutkittava teksti on viimeinen. Valituslaulujen sarja päättyy tutkittavaa tekstiä seuraavaan syntymäpäivän kiroamiseen jakeissa 14-18. Valituksen edellä kontekstina on joitakin kertomuksia Jeremiasta, mutta vasta jakeessa 20:2 Jeremia nimetään profeetaksi. Muuten valittaja on nimetön. Jeremia-kertomusten kehys on tässä toimituksellinen ja valituksen jälkeen seuraa deuteronomistista saarnaa Juudaa ja Jerusalemia vastaan. Tutkimus selvittää jakeiden 7-13 rakennetta, sisältöä ja tulkintaa ensin lähinnä laji- ja kirjallisuus- kriittisesti. Tutkimus osoittaa, että Jeremian valitus noudattaa yksilön valituslaulun kaavaa, mutta ei kuitenkaan yksiselitteisesti taivu lajin usein stereotyyppisiin tarkoituksiin. Suurin syy tähän on tekstin proosa- ja runomuodon vaihtelu ja sisällön hajanaisuus. Edes valituksen ydintä ei voi varmistaa, vaikka valituslaulun nuorimpina osina on tyypillisesti helppo pitää loppupuolen kollektiivisia lisiä. Varsinainen valitus on jakeissa 7-9 ja jakeet 10-13 ovat todennäköisimmin monivaiheinen päätössarja. Tutkimuksen keskeiset objektisuhdeteoreettiset peruskäsitteet sisäinen subjekti ja sisäinen objekti ovat ihmisen tiedostamattoman tason mielikuvia. Varhaisen tilan vuorovaikutusmielikuvien sisäisinä subjekteina ovat Riippuvainen ja Itseriittoinen. Ne ovat vaihtelevissa suhteissa Houkuttajan ja Hallitsijan muotoisia sisäisiä objekteja kohtaan. Myöhäisessä tilassa objekteille on syytä antaa uudet nimet: Vetäytyjä, Vaatija ja Parantaja. Tutkimus etenee osoittamalla tekstin ja SPT:n mukaisen mallin samankaltaisuuksia. Samalla on ollut mahdollista ottaa kantaa myös tekstin saumoihin ja tekstin syntyprosessiin. Tekstin objekti osoittautuu pääosin Hallitsijaksi, sillä Houkuttajan muotoisista jumaluuksista on kollektiivisesti pyritty tekemään pesäeroa Jerusalemin temppelin hävityksestä lähtien. Silti muistoista ja Houkuttajaksikin värittyneistä kaipuun ja pelon muodoista ei päästä eroon. Valituksen alkujakeita 7-9 leimaa Riippuvaisen masennus ja Itseriittoisen häpeä. Jakeissa 11-13 Hallitsijan muotoinen Jahve Sebaot tarjoaa hierarkkista symbioosia. Myöhäistä Vaatijaa ei tutkittavassa tekstissä ole kuin vanhurskaan käsitteenä, joka deuteronomistisessa teologiassa perustuu Jahven sanan kuulemiseen ja lain noudattamiseen. Tutkimus pyrkii osoittamaan, että kaikilla kokemuksilla on jollakin tavalla sekä yhteisöä että yksilöä eheyttäviä tarkoituksia. Kun valitus päättyy sarjaan vakuutuksia ja huipentuu kollektiiviseen ylistyskehotukseen, myös niillä on tarkoitus. Yksi osa tutkimustehtävää on ollut testata psykoanalyyttisen objektisuhdeteoreettisen metodin toimivuutta eksegeettisessä tutkimuksessa. Vaikka tulokset ovat suuntaa antavia, metodi on osoittautunut toimivaksi.

Responses of Scots pine to nickel and copper exposure and herbivory

The goal of this thesis was to examine the ecophysiological responses of Scots pine (Pinus sylvestris L.), with an emphasis on the oxidative enzyme peroxidase and plant phenolics to environmental stresses like elevated levels of nickel (Ni) and copper (Cu), and herbivory. The effects of Ni and Cu were studied in a gradient survey at a sulphur dioxide contaminated site in the Kola Peninsula, and with experiments in which seedlings were exposed to Ni mist or to Ni and Cu amended into the soil. In addition, experimental Ni exposure was combined with disturbance of the natural lichen cover of the forest ground layer. Pine sawfly attack was simulated in the early season defoliation experiment, in which mature Scots pine were defoliated (100 %) during two successive years in a dry, nutrient-poor Scots pine stand. In addition, the effect of previous defoliation on the growth of sawfly (Diprion pini L.) larvae was studied. Apoplastic peroxidase activity was elevated in the needles of pine in a Ni- , Cu- and SO2- polluted environment, which indicated an increased oxidative stress. Increased foliar peroxidase activity due to Ni contamination was shown in the experiment, in which Ni was added as mist. No such response was found in peroxidase acitivity of the roots exposed to elevated Ni and/or Cu in the soil. Elevated Ni in the soil increased the concentration of foliar condensed tannins, which are able to bind heavy metals in the cells. Addition of low levels of Ni in the soil appeared to benefit pine seedlings, which was seen as promoted shoot growth and better condition of the roots. Wet Ni deposition of 2000 mg m-2 reduced growth and survival of pine seedlings, whereas deposition levels 200 mg m-2 or 20 mg m-2 caused no effects in a 2-y lasting experiment. The lichen mat on the forest floor did not act as an effective buffer against the adverse impacts of heavy metals on pine seedlings. However, some evidence was found indicating that soil microbes profited from the lichen mat. Artificial defoliation increased peroxidase activity in the Scots pine needles. In addition, defoliation decreased nitrogen, diamine putrescine and glucose concentrations in the needles and increased the concentrations of several phenolic compounds, starch and sucrose. Previous artificial defoliation led to poor growth of sawfly larvae reared on the pines, suggesting delayed induced resistance in Scots pine. However, there was no consistent relationship between inducibility (proportional increase in a compound following defoliation) and adverse effects on the growth of pine sawfly larvae. The observed inducible responses in needle phenolics due to previous defoliation thus appear to represent non-specific responses against sawflies.

Carbon balance and component CO2 fluxes in boreal Scots pine stands

The forest vegetation takes up atmospheric carbon dioxide (CO2) in photosynthesis. Part of the fixed carbon is released back into the atmosphere during plant respiration but a substantial part is stored as plant biomass, especially in the stems of trees. Carbon also accumulates in the soil as litter and via the roots. CO2 is released into the atmosphere from these carbon stocks in the decomposition of dead biomass. Carbon balance of a forest stand is the difference between the CO2 uptake and CO2 efflux. This study quantifies and analyses the dynamics of carbon balance and component CO2 fluxes in four Southern Finnish Scots pine stands that covered the typical economic rotation time of 80 years. The study was based on direct flux measurements with chambers and eddy covariance (EC), and modelling of component CO2 fluxes. The net CO2 exchange of the stand was partitioned into component fluxes: photosynthesis of trees and ground vegetation, respiration of tree foliage and stems, and CO2 efflux from the soil. The relationships between the component fluxes and the environmental factors (light, temperature, atmospheric CO2, air humidity and soil moisture) were studied with mathematical modelling. The annual CO2 balance varied from a source of about 400 g C/m2 at a recently clearcut site to net CO2 uptake of 200 300 g C/m2 in a middle-aged (40-year-old) and a mature (75-year-old) stand. A 12-year-old sapling site was at the turning point from source to a sink of CO2. In the middle-aged stand, photosynthetic production was dominated by trees. Under closed pine canopies, ground vegetation accounted for 10 20% of stand photosynthesis whereas at the open sites the proportion and also the absolute photosynthesis of ground vegetation was much higher. The aboveground respiration was dominated by tree foliage which accounted for one third of the ecosystem respiration. Rate of wood respiration was in the order of 10% of total ecosystem respiration. CO2 efflux from the soil dominated the ecosystem respiratory fluxes in all phases of stand development. Instantaneous and delayed responses to the environmental driving factors could predict well within-year variability in photosynthetic production: In the short term and during the growing season photosynthesis follows primarily light while the seasonal variation is more strongly connected to temperature. The temperature relationship of the annual cycle of photosynthesis was found to be almost equal in the southern boreal zone and at the timberline in the northern boreal zone. The respiratory fluxes showed instantaneous and seasonal temperature relationships but they could also be connected to photosynthesis at an annual timescale.

Cytochrome P450-mediated drug interactions affecting lidocaine

Lidocaine is a widely used local anaesthetic agent that also has anti-arrhythmic effects. It is classified as a type Ib anti-arrhythmic agent and is used to treat ventricular tachycardia or ventricular fibrillation. Lidocaine is eliminated mainly by metabolism, and less than 5% is excreted unchanged in urine. Lidocaine is a drug with a medium to high extraction ratio, and its bioavailability is about 30%. Based on in vitro studies, the earlier understanding was that CYP3A4 is the major cytochrome P450 (CYP) enzyme involved in the metabolism of lidocaine. When this work was initiated, there was little human data on the effect of inhibitors of CYP enzymes on the pharmacokinetics of lidocaine. Because lidocaine has a low therapeutic index, medications that significantly inhibit lidocaine clearance (CL) could increase the risk of toxicity. These studies investigated the effects of some clinically important CYP1A2 and CYP3A4 inhibitors on the pharmacokinetics of lidocaine administered by different routes. All of the studies were randomized, double-blind, placebo-controlled cross-over studies in two or three phases in healthy volunteers. Pretreatment with clinically relevant doses of CYP3A4 inhibitors erythromycin and itraconazole or CYP1A2 inhibitors fluvoxamine and ciprofloxacin was followed by a single dose of lidocaine. Blood samples were collected to determine the pharmacokinetic parameters of lidocaine and its main metabolites monoethylglycinexylidide (MEGX) and 3-hydroxylidocaine (3-OH-lidocaine). Itraconazole and erythromycin had virtually no effect on the pharmacokinetics of intravenous lidocaine, but erythromycin slightly prolonged the elimination half-life (t½) of lidocaine (Study I). When lidocaine was taken orally, both erythromycin and itraconazole increased the peak concentration (Cmax) and the area under the concentration-time curve (AUC) of lidocaine by 40-70% (Study II). Compared with placebo and itraconazole, erythromycin increased the Cmax and the AUC of MEGX by 40-70% when lidocaine was given intravenously or orally (Studies I and II). The pharmacokinetics of inhaled lidocaine was unaffected by concomitant administration of itraconazole (Study III). Fluvoxamine reduced the CL of intravenous lidocaine by 41% and prolonged the t½ of lidocaine by 35%. The mean AUC of lidocaine increased 1.7-fold (Study IV). After oral administration of lidocaine, the mean AUC of lidocaine in-creased 3-fold and the Cmax 2.2-fold by fluvoxamine (Study V). During the pretreatment with fluvoxamine combined with erythromycin, the CL of intravenous lidocaine was 53% smaller than during placebo and 21% smaller than during fluvoxamine alone. The t½ of lidocaine was significantly longer during the combination phase than during the placebo or fluvoxamine phase. The mean AUC of intravenous lidocaine increased 2.3-fold and the Cmax 1.4-fold (Study IV). After oral administration of lidocaine, the mean AUC of lidocaine increased 3.6-fold and the Cmax 2.5-fold by concomitant fluvoxamine and erythromycin. The t½ of oral lidocaine was significantly longer during the combination phase than during the placebo (Study V). When lidocaine was given intravenously, the combination of fluvoxamine and erythromycin prolonged the t½ of MEGX by 59% (Study IV). Compared with placebo, ciprofloxacin increased the mean Cmax and AUC of intravenous lidocaine by 12% and 26%, respectively. The mean plasma CL of lidocaine was reduced by 22% and its t½ prolonged by 7% (Study VI). These studies clarify the principal role of CYP1A2 and suggest only a modest role of CYP3A4 in the elimination of lidocaine in vivo. The inhibition of CYP1A2 by fluvoxamine considerably reduces the elimination of lidocaine. Concomitant use of fluvoxamine and the CYP3A4 inhibitor erythromycin further increases lidocaine concentrations. The clinical implication of this work is that clinicians should be aware of the potentially increased toxicity of lidocaine when used together with inhibitors of CYP1A2 and particularly with the combination of drugs inhibiting both CYP1A2 and CYP3A4 enzymes.

Interaction of alcohol and smoking in the pathogenesis of upper digestive tract cancers - possible chemoprevention with cysteine

Background: Alcohol consumption and smoking are the main causes of upper digestive tract cancers. These risk factors account for over 75% of all cases in developed countries. Epidemiological studies have shown that alcohol and tobacco interact in a multiplicative way to the cancer risk, but the pathogenetic mechanism behind this is poorly understood. Strong experimental and human genetic linkage data suggest that acetaldehyde is one of the major factors behind the carcinogenic effect. In the digestive tract, acetaldehyde is mainly formed by microbial metabolism of ethanol. Acetaldehyde is also a major constituent of tobacco smoke. Thus, acetaldehyde from both of these sources may have an interacting carcinogenic effect in the human upper digestive tract. Aims: The first aim of this thesis was to investigate acetaldehyde production and exposure in the human mouth resulting from alcohol ingestion and tobacco smoking in vivo. Secondly, specific L-cysteine products were prepared to examine their efficacy in the binding of salivary acetaldehyde in order to reduce the exposure of the upper digestive tract to acetaldehyde. Methods: Acetaldehyde levels in saliva were measured from human volunteers during alcohol metabolism, during tobacco smoking and during the combined use of alcohol and tobacco. The ability of L-cysteine to eliminate acetaldehyde during alcohol metabolism and tobacco smoking was also investigated with specifically developed tablets. Also the acetaldehyde production of Escherichia coli - an important member of the human microbiota - was measured in different conditions prevailing in the digestive tract. Results and conclusions: These studies established that smokers have significantly increased acetaldehyde exposure during ethanol consumption even when not actively smoking. Acetaldehyde exposure was dramatically further increased during active tobacco smoking. Thus, the elevated aerodigestive tract cancer risk observed in smokers and drinkers may be the result of the increased acetaldehyde exposure. Acetaldehyde produced in the oral cavity during ethanol challenge was significantly decreased by a buccal L-cysteine -releasing tablet. Also smoking-derived acetaldehyde could be totally removed by using a tablet containing L-cysteine. In conclusion, this thesis confirms the essential role of acetaldehyde in the pathogenesis of alcohol- and smoking-induced cancers. This thesis presents a novel experimental approach to decrease the local acetaldehyde exposure of the upper digestive tract with L-cysteine, with the eventual goal of reducting the prevalence of upper digestive tract cancers.

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.

Egyptin kristillisten kirjureiden jäljillä : Tutkimus 100- ja 200-lukujen Uuden testamentin kanonisten ja apokryfisten käsikirjoitusten ulkoisista piirteistä

Tutkimukseni tarkoituksena on tutkia kaikkein varhaisimpia Uuden testamentin kanonisia ja apokryfisia käsikirjoituksia sekä niiden kirjureita. Huomion keskipisteenä ovat kyseisten käsikirjoitusten ulkoiset piirteet, kuten esimerkiksi kirjoitusmateriaali, muoto, koko ja käsiala. Näiden avulla vertaan kanonisia käsikirjoituksia apokryfisiin ja pyrin selvittämään, erosivatko näiden kopiointimenetelmät toisistaan. Yksi keskeisimmistä kysymyksistä on se, voidaanko ulkoisten piirteiden avulla päätellä jotain käsikirjoitusten asemasta ja arvostuksesta. Tutkimuksen aluksi esittelen tutkimusaineistoni käsikirjoitukset ja tekstit. Päädyin vertaamaan kanonisia evankeliumeita kaikkiin 100- ja 200-luvuilta löydettyihin apokryfisiin käsikirjoituksiin, joihin sisältyy esimerkiksi Tuomaan ja Pietarin evankeliumit sekä Hermaan paimen. Kaikki tämän ajanjakson kristilliset käsikirjoitukset ovat löytyneet Egyptistä, minkä vuoksi tutkimukseni keskittyy Egyptiin ja sen kirjureihin. Ennen varsinaista käsikirjoitusten analyysiä käsittelen käsikirjoitusten löytöpaikkoja, kaanonin sekä antiikin kirjureiden historiaa. Ensimmäiseksi käsittelen käsikirjoitusten materiaalia, eli papyrusta ja pergamenttia. Tässä suhteessa kanoniset käsikirjoitukset eivät eroa apokryfisista, vaan aineistot ovat tämän suhteen identtisiä. Tämän jälkeen huomio kiinnittyy käsikirjoitusten muotoon, eli siihen kirjoitettiinko käsikirjoitukset koodeksiin vai kääröön. Analyysin edetessä paljastuu, että apokryfisissa käsikirjoituksissa käytettiin useammin käärömuoto kuin kanonisissa käsikirjoituksissa. Voidaan esittää, että kristityt kirjoittivat koodeksiin kaikkein arvostetuimmat tekstit, joten käärömuoto voi kertoa käsikirjoituksen sisältävän tekstin alemmasta arvostuksesta. Tutkimuksen seuraavissa osioissa käsitellään koodeksien kokoa, marginaaleja, palstoja sekä käsialan kokoa. Lukujen perusteella voidaan sanoa, että kanoniset koodeksit muodostavat hieman yhtenäisemmän linjan kuin apokryfiset koodeksit. Kanonisten koodeksien kirjureiden toimintatavat ovat siis olleet hieman yhtenäisempiä. Käsikirjoitusten käsialan tarkempi analyysi paljastaa kuitenkin, että niin kanoniset kuin apokryfiset käsikirjoitukset kirjoitettiin suhteellisen hyvällä käsialalla. Tutkimuksen viimeisessä luvussa käy ilmi, että apokryfisten koodeksien epäyhtenäisyys johtuu osittain niiden erilaisista käyttötarkoituksista. Apokryfisia koodekseja valmistettiin enemmän kristittyjen henkilökohtaiseen käyttöön verrattuna kanonisiin koodekseihin. Tästä huolimatta suurin osa käsikirjoituksista oli seurakuntien liturgisessa käytössä. Toisin sanoen niin kanonisia evankeliumeita kuin apokryfisia tekstejä luettiin ääneen seurakuntien kokoontumisissa, mikä kertoo niiden arvosta.

Hirsitaloteollisuuden kehityshaasteet

Pientalobarometri 2/2008 ennustaa omakotitalorakentamisen jatkavan laskuaan rakentamiskustannusten kasvamisesta, kaavoituksesta, tonttitarjonnasta ja talouden tilasta johtuen. Kustannusten odotetaan edelleen nousevan mm. energia­tehokkuuden kohentumisen myötä. Työ- ja elinkeinoministeriön Puutalojen ja rakennuspuusepäntuotteiden valmistus –toimialaraportissa 2008 oletetaan myös, että lämmöneristysvaatimukset ovat saattaneet lisätä massiivihirsitalojen kysyntää, koska uusien määräysten voimaantulon jälkeen niitä ei mahdollisesti enää tehdä. Kehityksen voidaan olettaa johtavan rakennusten koon ja varustetason järkevöittämiseen. Oma­koti­talorakentamisen tarpeeksi pientalobarometri laskee 20 000 asuntoaloitusta, mutta toimialaraportissa määrän arvioidaan vuonna 2008 jäävän 12 500 oma­kotitalon aloitukseen. Avaimet käteen –rakentaminen on kasvusuunnassa ja talo­paketit ovat kehittymässä selvemmiksi rakennusosakokonaisuuksiksi. Pientalobarometri kertoo suomalaisten toivovan yksilöllisyyttä. Talotehtaiden toimituksista yksilöllisiä suunnitteluratkaisuja on kolmannes ja tyyppimuunnoksia puolet. Valmisosatalojen osuus asunnoista on noin 68 % ja teollisen hirren osuus valmisosatalojen markkinoista on nyt kutakuinkin samoissa 10 % lukemissa kuin 20 vuotta sitten. Korkeimmillaan teollisen hirren osuus valmisosataloista kävi 17 % tasolla kymmenen vuotta sitten, vuosina 1995 ja 1996. Siporex-, betoni,- tiili- ja harkkotalojen osuus on noussut kahdessakymmenessä vuodessa 4 %:sta 12 %:iin ja precut-talojen osuus 2 %:sta 16 %:iin, kun taas puuelementtien osuus on laskenut 85 %:sta 62 %:iin. Talopaketin keskimääräinen kuluttajahinta on Toimialaraportin mukaan noin 83 000 euroa ja niitä valmistuu vuodessa alle 10 000. Talopakettimarkkinat ovat Pientalobarometrin mukaan vuonna 2008 hieman laskeneet vuosien 2006 ja 2007 huippulukemista alle 800 miljoonan euron. Teollisten hirsivalmistajien liikevaihto laski myös vuodesta 2007 alle 350 miljoonan. Toimialaraportin mukaan puutalojen valmistus työllistää vajaa 4000 henkeä 251 toimipaikassa (2006). Alan liikevaihto vuonna 2006 oli 812 miljoonaa euroa ja viennin arvo 178 miljoonaa euroa. Viennin kasvun todettiin riippuvan hirsitaloteollisuudesta. Viennin kannalta tärkeitä alueita ovat Keski-Eurooppa, Venäjä, Japani ja Pohjoismaat. Puutalojen vienti on Toimialaraportin mukaan kohonnut 90-luvun alun noin 30 miljoonasta yli 200 miljoonaan euroon, josta hirsitalojen viennin arvo ylittää 160 miljoonaa. Tutkimus- ja kehittämiskuluiksi arvioidaan puutalon valmistajilla 0–2 % tuotannon arvosta. Puutalojen mediaanikäyttökate oli Toimialaraportin mukaan vuonna 2006 noin 6 % kun teollisuuden vastaava luku on 10 %. Finnveran tilastointi hirsitalojen kustannusrakenteesta ja kannattavuudesta ei poikkea tästä, vaan hirsitalojen käyttökatteeksi ilmoitetaan 6,4 % ja kokonaistulokseksi 3,4 % vuonna 2007. Toimialaraportin mukaan teollisuuden omavaraisuusaste on noin 43 % kun taas puutaloteollisuuden omavaraisuusaste jää 26,5 %:iin ja hirsitalojen Finnveran mukaan 27,7 %:iin. Hirsitaloja valmistaa Toimialaraportin mukaan noin 150 yritystä. Alan kahden suurimman yrityksen osuus on lähes puolet koko alan liikevaihdosta.

Oral health and menopause

Hormone therapy (HT) is widely used to relieve climacteric symptoms in order to increase the well-being of the women. The benefits as well as side-effects of HT are well documented. The principal menopausal oral symptoms are dry mouth (DM) and sensation of painful mouth (PM) due to various causes. Profile studies have indicated that HT users are more health-conscious than non-users. The hypothesis of the present study was that there are differences in oral health between woman using HT and those not using HT. A questionnaire study of 3173 women of menopausal age (50-58 years old) was done to investigate the prevalence of self-assessed sensations of PM and DM. Of those women participating in the questionnaire study, a random sample of 400 (200 using, 200 not using HT) was examined clinically in a 2-year follow-up study. Oral status was recorded according to WHO methods using DMFT and CPITN indices. The saliva flows were measured, salivary total protein, albumin and immunoglobulin concentrations and selected periodontal micro-organisms were analysed, and panoramic tomography of the jaws was taken. The patients filled in a structured questionnaire on their systemic health, medication and health habits. According to our questionnaire study there was no significant difference in the occurrence of self- assessed PM or DM between the HT users and non-users. According to logistic regression analyses, climacteric complaints significantly correlated with the occurrence of PM (p=0.000) and DM (p=0.000) irrespective of the use of HT, indicating that PM and DM are associated with climacteric symptoms in general. There was no difference between the groups in DMFT index values at follow up. The number of filled teeth (FT) showed a significant (p<0.05) increase in the HT group at follow-up. Periodontitis was diagnosed in 79% of HT users at baseline and in 71% at the follow-up. The values for non-HT users were 80% vs. 76%, respectively (Ns.). The mean numbers of ≥ 6 mm deep periodontal pockets were 0.9 ± 1.7 at baseline vs. 1.1 ± 2.1 two years later in the HT group, and 1.0 ± 1.7 vs. 1.2 ± 1.9, respectively, in the non-HT group. In a large Finnish national health survey, the prevalence of peridontitis of women of this age group was lower, but the prevalence of severe periodontitis seemed to be higher than in our study. Salivary albumin, IgG and IgM concentrations decreased in the HT group during the 2-year follow up (p<0.05), possibly indicating an improvement in epithelial integrity. No difference was found in any other salivary parameters or in the prevalence of the periodontal bacteria between or within the groups. In conclusion, the present findings showed that 50 to 58 year old women living in Helsinki have fairly good oral and dental health. The occurrence of PM and DM seemed to be associated with climacteric symptoms in general, and the use of HT did not affect the oral symptoms studied.

The Proto-Lucianic Problem in 1 Samuel

The Lucianic text of the Septuagint of the Historical Books witnessed primarily by the manuscript group L (19, 82, 93, 108, and 127) consists of at least two strata: the recensional elements, which date back to about 300 C.E., and the substratum under these recensional elements, the proto-Lucianic text. Some distinctive readings in L seem to be supported by witnesses that antedate the supposed time of the recension. These witnesses include the biblical quotations of Josephus, Hippolytus, Irenaeus, Tertullian, and Cyprian, and the Old Latin translation of the Septuagint. It has also been posited that some Lucianic readings might go back to Hebrew readings that are not found in the Masoretic text but appear in the Qumran biblical texts. This phenomenon constitutes the proto-Lucianic problem. In chapter 1 the proto-Lucianic problem and its research history are introduced. Josephus references to 1 Samuel are analyzed in chapter 2. His agreements with L are few and are mostly only apparent or, at best, coincidental. In chapters 3 6 the quotations by four early Church Fathers are analyzed. Hippolytus Septuagint text is extremely hard to establish since his quotations from 1 Samuel have only been preserved in Armenian and Georgian translations. Most of the suggested agreements between Hippolytus and L are only apparent or coincidental. Irenaeus is the most trustworthy textual witness of the four early Church Fathers. His quotations from 1 Samuel agree with L several times against codex Vaticanus (B) and all or most of the other witnesses in preserving the original text. Tertullian and Cyprian agree with L in attesting some Hebraizing approximations that do not seem to be of Hexaplaric origin. The question is more likely of early Hebraizing readings of the same tradition as the kaige recension. In chapter 7 it is noted that Origen, although a pre-Lucianic Father, does not qualify as a proto-Lucianic witness. General observations about the Old Latin witnesses as well as an analysis of the manuscript La115 are given in chapter 8. In chapter 9 the theory of the proto-Lucianic recension is discussed. In order to demonstrate the existence of the proto-Lucianic recension one should find instances of indisputable agreement between the Qumran biblical manuscripts and L in readings that are secondary in Greek. No such case can be found in the Qumran material in 1 Samuel. In the text-historical conclusions (chapter 10) it is noted that of all the suggested proto-Lucianic agreements in 1 Samuel (about 75 plus 70 in La115) more than half are only apparent or, at best, coincidental. Of the indisputable agreements, however, 26 are agreements in the original reading. In about 20 instances the agreement is in a secondary reading. These agreements are early variants; mostly minor changes that happen all the time in the course of transmission. Four of the agreements, however, are in a pre-Hexaplaric Hebraizing approximation that has found its way independently into the pre-Lucianic witnesses and the Lucianic recension. The study aims at demonstrating the value of the Lucianic text as a textual witness: under the recensional layer(s) there is an ancient text that preserves very old, even original readings which have not been preserved in B and most of the other witnesses. The study also confirms the value of the early Church Fathers as textual witnesses.