Clinical Phenotype and Genetic Epidemiology of Schizophrenia in a Finnish Isolate

This study is part of the joint project "The Genetic Epidemiology and Molecular Genetics of schizophrenia in Finland" between the Departments of Mental Health and Alcohol Research, and Molecular Medicine at the National Public Health Institute. In the study, we utilized three nationwide health care registers: 1) the Hospital Discharge Register, 2) the Free Medication Register, and 3) the Disability Pension Register, plus the National Population Register, in order to identify all patients with schizophrenia born from 1940 to 1976 (N=33,731) in Finland, and their first degree-relatives. 658 patients with at least one parent born in a homogeneous isolate in northeastern Finland were identified, as well as 4904 familial schizophrenia patients with at least two affected siblings from the whole country. The comparison group was derived from the Health 2000 Study. We collected case records and reassessed the register diagnosis. Were contacted the isolate patients and a random sample of patients from the whole country to make diagnostic clinical interviews and to assess the negative and positive symptoms and signs of schizophrenia. In addition to these patients, we interviewed siblings who were initially healthy according to the Hospital Discharge Register. Of those with a register diagnosis of schizophrenia, schizoaffective or schizophreniform disorder, 69% received a record-based consensus diagnosis and 63% an interview-based diagnosis of schizophrenia. Patients with schizophrenia having first-degree relatives with psychotic disorder had more severe affective flattening and alogia than those who were the only affected individuals in their family. The novel findings were: 1) The prevalence of schizophrenia in the isolate was relatively high based on register (1.5%), case record (0.9-1.3%), and interview (0.7-1.2%) data. 2) Isolate patients, regardless of their familial loading for schizophrenia, had less delusions and hallucinations than the whole country familial patients, which may be related to the genetic homogeneity in the isolate. This phenotype encourages the use of endophenotypes in genetic analyses instead of diagnoses alone. 3) The absence of register diagnosis does not confirm that siblings are healthy, because 7.7% of siblings had psychotic symptoms already before the register diagnoses were identified in 1991. For genetic research, the register diagnosis should therefore be reassessed using either a structured interview or a best- estimate case note consensus diagnosis. Structured clinical interview methods need be considered also in clinical practice.

Cyclosporine population pharmacokinetics in pediatric renal transplant recipients

Cyclosporine is an immunosuppressant drug with a narrow therapeutic index and large variability in pharmacokinetics. To improve cyclosporine dose individualization in children, we used population pharmacokinetic modeling to study the effects of developmental, clinical, and genetic factors on cyclosporine pharmacokinetics in altogether 176 subjects (age range: 0.36–20.2 years) before and up to 16 years after renal transplantation. Pre-transplantation test doses of cyclosporine were given intravenously (3 mg/kg) and orally (10 mg/kg), on separate occasions, followed by blood sampling for 24 hours (n=175). After transplantation, in a total of 137 patients, cyclosporine concentration was quantified at trough, two hours post-dose, or with dose-interval curves. One-hundred-four of the studied patients were genotyped for 17 putatively functionally significant sequence variations in the ABCB1, SLCO1B1, ABCC2, CYP3A4, CYP3A5, and NR1I2 genes. Pharmacokinetic modeling was performed with the nonlinear mixed effects modeling computer program, NONMEM. A 3-compartment population pharmacokinetic model with first order absorption without lag-time was used to describe the data. The most important covariate affecting systemic clearance and distribution volume was allometrically scaled body weight i.e. body weight**3/4 for clearance and absolute body weight for volume of distribution. The clearance adjusted by absolute body weight declined with age and pre-pubertal children (< 8 years) had an approximately 25% higher clearance/body weight (L/h/kg) than did older children. Adjustment of clearance for allometric body weight removed its relationship to age after the first year of life. This finding is consistent with a gradual reduction in relative liver size towards adult values, and a relatively constant CYP3A content in the liver from about 6–12 months of age to adulthood. The other significant covariates affecting cyclosporine clearance and volume of distribution were hematocrit, plasma cholesterol, and serum creatinine, explaining up to 20%–30% of inter-individual differences before transplantation. After transplantation, their predictive role was smaller, as the variations in hematocrit, plasma cholesterol, and serum creatinine were also smaller. Before transplantation, no clinical or demographic covariates were found to affect oral bioavailability, and no systematic age-related changes in oral bioavailability were observed. After transplantation, older children receiving cyclosporine twice daily as the gelatine capsule microemulsion formulation had an about 1.25–1.3 times higher bioavailability than did the younger children receiving the liquid microemulsion formulation thrice daily. Moreover, cyclosporine oral bioavailability increased over 1.5-fold in the first month after transplantation, returning thereafter gradually to its initial value in 1–1.5 years. The largest cyclosporine doses were administered in the first 3–6 months after transplantation, and thereafter the single doses of cyclosporine were often smaller than 3 mg/kg. Thus, the results suggest that cyclosporine displays dose-dependent, saturable pre-systemic metabolism even at low single doses, whereas complete saturation of CYP3A4 and MDR1 (P-glycoprotein) renders cyclosporine pharmacokinetics dose-linear at higher doses. No significant associations were found between genetic polymorphisms and cyclosporine pharmacokinetics before transplantation in the whole population for which genetic data was available (n=104). However, in children older than eight years (n=22), heterozygous and homozygous carriers of the ABCB1 c.2677T or c.1236T alleles had an about 1.3 times or 1.6 times higher oral bioavailability, respectively, than did non-carriers. After transplantation, none of the ABCB1 SNPs or any other SNPs were found to be associated with cyclosporine clearance or oral bioavailability in the whole population, in the patients older than eight years, or in the patients younger than eight years. In the whole population, in those patients carrying the NR1I2 g.-25385C–g.-24381A–g.-205_-200GAGAAG–g.7635G–g.8055C haplotype, however, the bioavailability of cyclosporine was about one tenth lower, per allele, than in non-carriers. This effect was significant also in a subgroup of patients older than eight years. Furthermore, in patients carrying the NR1I2 g.-25385C–g.-24381A–g.-205_-200GAGAAG–g.7635G–g.8055T haplotype, the bioavailability was almost one fifth higher, per allele, than in non-carriers. It may be possible to improve individualization of cyclosporine dosing in children by accounting for the effects of developmental factors (body weight, liver size), time after transplantation, and cyclosporine dosing frequency/formulation. Further studies are required on the predictive value of genotyping for individualization of cyclosporine dosing in children.

Intonation of Finnish Verbs

A production experiment investigated the tonal shape of Finnish finite verbs in transitive sentences without narrow focus. Traditional descriptions of Finnish stating that non- focused finite verbs do not receive accents were only partly supported. Verbs were found to have a consistently smaller pitch range than words in other word classes, but their pitch contours were neither flat nor explainable by pure interpolation.

Toward a widely usable finite-state morphology workbench for less studied languages, 1: Desiderata

Most of the world’s languages lack electronic word form dictionaries. The linguists who gather such dictionaries could be helped with an efficient morphology workbench that adapts to different environments and uses. A widely usable workbench could be characterized, ideally, as generally applicable, extensible, and freely available (GEA). It seems that such a solution could be implemented in the framework of finite-state methods. The current work defines the GEA desiderata and starts a series of articles concerning these desiderata in finite- state morphology. Subsequent parts will review the state of the art and present an action plan toward creating a widely usable finite-state morphology workbench.

Validiusargumentin rakentuminen suullisen kielitaidon arviointiprojektissa

Artikkelissa kuvataan aluksi kielitaidon arvioinnin validiustutkimuksen keskeisiä suuntauksia, joilla kehystetään käynnissä olevan suullisen kielitaidon arviointihankkeen tutkimustehtävä. Tutkimustehtävä kohdentuu kansallisiin opetussuunnitelmaperusteisiin sisältyvän taitotasoasteikon validiuteen, jota tarkastellaan validiusargumentin rakentumisen näkökulmasta. Väitettä asteikon ja sen pohjalta laadittujen puhetehtävien pätevyydestä suullisen taidon mittareina koetellaan Toulminin mallin avulla asettamalla tätä johtopäätöstä tukevat empiiriset lähtötiedot ja niitä tukevat perusteet vastakkain väitettä horjuttavan näytön kanssa. Perusteet ja varaukset koskevat väitetyn johtopäätöksen relevanssia, hyödyllisyyttä, tarkoitettuja seurauksia ja riittävyyttä. Hankkeen tutkijoiden spesifit tutkimusongelmat kohdentuvat johonkin mainituista piirteistä. Validiusargumenttia sovelletaan suullisen kielitaidon arviointihankkeen, Hy-Talkin, kontekstissa. Ongelmanasettelussa ja menetelmävalinnoissa hyödynnetään validiustutkimuksen perinteisempiä sisältö- ja kriteeriperustaisia lähestymistapoja, mutta tehdään myös uusia avauksia tiedon syventämiseksi niistä tulkinnoista ja näkemyksistä, joita suullisten tehtävien suorittajilla ja arvioijilla ilmenee.

Sijasynkretismi morfologian koetinkivenä

Syncretism and the overlapping of morphologi- cally distinct units or entire categories have different influences on morphosyntactically cumulative and less cumulative forms. The Finnic languages, in comparison to the more eastern Finno-Ugric languages, mainly display morphologically less complex forms. Morphologically there is a clear distinction in the way syncretism is manifested in the Finnic languages that, consequently, is one of the most distinct features in the inflectional system despite the close ge- nealogical affinity. This can concretely be seen in the differences in the case inflection of the southern, such as Livonian, Estonian and Votic, and northern Finnic languages, most notably Finnish, Karelian and Veps. The comparison of syncretism in these languages shows both cross-linguistic regularity and language-specific rules that determine syncretic forms. Diachronic change and the erosion of suffixal ele- ments are closely involved in the rise of syncretism. The paper exam- ines the symmetries and asymmetries in the occurrence of syncretic forms in Finnic case paradigms.

Participes présents et gérondifs en traduction finnoise : perte ou changement de valeur ?

Les participes présents apparaissent, entre autres, dans des constructions à prédication seconde détachées : (1) Intervenant hier soir à Ankara, […], Vladimir Poutine s’est risqué à […]. (Le Figaro 7.12.2004 : 4) Même si les gérondifs, formes adverbiales du verbe (« converbes », cf. Haspelmath & König 1995), n’ont pas d’incidence nominale, contrairement aux participes présents, formes adjectivales du verbe, et ne sont donc pas toujours comptés parmi les constructions à prédication seconde (p.ex. Neveu 1998), les deux ont des emplois assez proches : dans des énoncés du type (2a-b), le participe adjoint peut être paraphrasé par un gérondif, même si son statut fonctionnel n’est pas le même (Halmøy, 2003 : 156-157) : (2a) Arrivant à Paris, Emile a proposé à Léa de [...]. (2b) En arrivant à Paris, Emile a proposé à Léa de[...]. (Halmøy, 2003 : 157) Le finnois ne connaît ni ce genre de constructions détachés ni de forme appelée ‘gérondif’, et les deux participes présents finnois (actif et passif) ne correspondent jamais à un participe présent détaché français : en plus de subordonnées, on trouve à leur place le deuxième infinitif, soit à l’inessif, soit à l’instructif, formes nominales qu’on trouve également dans la traduction des gérondifs : (3a) […] ? me demanda-t-elle sèchement en me montrant l’une des lignes incriminées. (Nothomb, p. 62) […] : hän kysyi minulta kuivakkaasti näyttäen erästä Unajin moittimaa riviä. (Suni, p. 4) (3b) L’espace d’un instant, il sourit, croyant que […] je m’étais trompée de commodités. (Nothomb, p. 138-139) Hetken hän hymyili luullen, että minä […] olin erehtynyt mukavuuslaitoksesta. (Suni, p. 94) : Dans cette communication, nous examinerons quatre traductions littéraires en nous demandant dans quels cas et de quelle manière la différence entre le participe et le gérondif a éventuellement été prise en considération.

Three-year-olds are sensitive to semantic prominence during online language comprehension

Recent evidence from adult pronoun comprehension suggests that semantic factors such as verb transitivity affect referent salience and thereby anap- hora resolution. We tested whether the same semantic factors influence pronoun comprehension in young children. In a visual world study, 3-year- olds heard stories that began with a sentence containing either a high or a low transitivity verb. Looking behaviour to pictures depicting the subject and object of this sentence was recorded as children listened to a subsequent sentence containing a pronoun. Children showed a stronger preference to look to the subject as opposed to the object antecedent in the low transitivity condition. In addition there were general preferences (1) to look to the subject in both conditions and (2) to look more at both potential antecedents in the high transitivity condition. This suggests that children, like adults, are affected by semantic factors, specifically semantic prominence, when interpreting anaphoric pronouns.