Cognitive Functioning in Young Adults with Depression, Anxiety Disorders, or Burnout Symptoms : Findings from a Population-based Sample

Background. Evidence of cognitive dysfunction in depressive and anxiety disorders is growing. However, the neuropsychological profile of young adults has received only little systematic investigation, although depressive and anxiety disorders are major public health problems for this age group. Available studies have typically failed to account for psychiatric comorbidity, and samples derived from population-based settings have also seldom been investigated. Burnout-related cognitive functioning has previously been investigated in only few studies, again all using clinical samples and wide age groups. Aims. Based on the information gained by conducting a comprehensive review, studies on cognitive impairment in depressive and anxiety disorders among young adults are rare. The present study examined cognitive functioning in young adults with a history of unipolar depressive or anxiety disorders in comparison to healthy peers, and associations of current burnout symptoms with cognitive functioning, in a population-based setting. The aim was also to determine whether cognitive deficits vary as a function of different disorder characteristics, such as severity, psychiatric comorbidity, age at onset, or the treatments received. Methods. Verbal and visual short-term memory, verbal long-term memory and learning, attention, psychomotor processing speed, verbal intelligence, and executive functioning were measured in a population-based sample of 21-35 year olds. Performance was compared firstly between participants with pure non-psychotic depression (n=68) and healthy peers (n=70), secondly between pure (n=69) and comorbid depression (n=57), and thirdly between participants with anxiety disorders (n=76) and healthy peers (n=71). The diagnostic procedure was based on the SCID interview. Fourthly, the associations of current burnout symptoms, measured with the Maslach Burnout Inventory General Survey, and neuropsychological test performance were investigated among working young adults (n=225). Results. Young adults with depressive or anxiety disorders, with or without psychiatric comorbidity, were not found to have major cognitive impairments when compared to healthy peers. Only mildly compromised verbal learning was found among depressed participants. Pure and comorbid depression groups did not differ in cognitive functioning, either. Among depressed participants, those who had received treatment showed more impaired verbal memory and executive functioning, and earlier onset corresponded with more impaired executive functioning. In anxiety disorders, psychotropic medication and low psychosocial functioning were associated with deficits in executive functioning, psychomotor processing speed, and visual short-term memory. Current burnout symptoms were associated with better performance in verbal working memory and verbal intelligence. However, lower examiner-rated social and occupational functioning was associated with problems in verbal attention, memory, and learning. Conclusions. Depression, anxiety disorders, or burnout symptoms may not be associated with major cognitive deficits among young adults derived from the general population. Even psychiatric comorbidity may not aggravate cognitive functioning in depressive or anxiety disorders among these young adults. However, treatment-seeking in depression was found to be associated with cognitive deficits, suggesting that these deficits relate to increased distress. Additionally, early-onset depression, found to be associated with executive dysfunction, may represent a more severe form of the disorder. In anxiety disorders, those with low symptom-related psychosocial functioning may have cognitive impairment. An association with self-reported burnout symptoms and cognitive deficits was not detected, but individuals with low social and occupational functioning may have impaired cognition.

Temporomandibular disorders and related psychosocial factors in non-patients : A survey and a clinical follow-up study based on the RDC/TMD

Temporomandibular disorders (TMD) and psychosocial factors reportedly associate. The underlying factors remain partially obscure, however, and further studies are required to clarify the relationships. The aims of this study were thus to assess in a non-patient working population the prevalence of TMD and related symptoms, and to clinically diagnose and follow the natural courses of TMD over a one-year period. In addition, possible comorbidity of temporomandibular and/or neck muscle pain and perceived stress and their impact on work performance were investigated, as well as how various psychosocial aspects relate to TMD. A questionnaire was mailed to all 30- to 55-year-old employees of the Finnish Broadcasting Company Ltd. whose employment in the Helsinki area had lasted at least five years (n = 1784). Of the 1339 subjects, who returned the questionnaire, 241 were examined according to the RDC/TMD and standard neck muscle palpation methods. Clinical signs of temporomandibular and/or neck muscle pain were found in 118 subjects. One-year follow-up TMD examinations were conducted on 211 subjects. The prevalence of frequent painless TMJ-related symptoms was 10%, orofacial pain 7%, neck pain 38%, and headache 15%. TMD diagnoses were: myofascial pain (13%), disc displacements (16%), and arthralgia, osteoarthritis, osteoarthrosis (4%). Chronic myofascial pain was present in 7% and chronic disc displacement with reduction in 11% of the subjects. Symptoms were significantly associated with almost all the studied psychosocial symptoms. Reduced work performance was significantly positively associated with continuous pain, severity of pain, and health stress perception, and according to logistic regression, somatization with the probability of having chronic myofascial pain. It could be concluded based on the results of this study among a non-patient working population that TMD and related symptoms are common and associated with psychosocial factors. Moreover, myofascial pain and disc displacement with reduction are the most common diagnoses of TMD. In addition, self-reported health related stress, and continuous pain in temporomandibular and/or neck muscles are associated with reduced work performance, and somatization is significantly associated with chronic myofascial pain.

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.

Molecular Genetics of Schizophrenia and Related Intermediate Phenotypes in a Founder Population

Schizophrenia, affecting about 1% of population worldwide, is a severe mental disorder characterized by positive and negative symptoms, such as psychosis and anhedonia, as well as cognitive deficits. At present, schizophrenia is considered a complex disorder of neurodevelopmental origin with both genetic and environmental factors contributing to its onset. Although a number of candidate genes for schizophrenia have been highlighted, only very few schizophrenia patients are likely to share identical genetic liability. This study is based on the nation-wide schizophrenia family sample of the National Institute for Health and Welfare, and represents one of the largest and most well-characterized familial series in the world. In the first part of this study, we investigated the roles of the DTNBP1, NRG1, and AKT1 genes in the background of schizophrenia in Finland. Although these genes are associated with schizophrenia liability in several populations, any significant association with clinical diagnostic information of schizophrenia remained absent in our sample of 441 schizophrenia families. In the second part of this study, we first replicated schizophrenia linkage on the long arm of chromosome 7 in 352 schizophrenia families. In the following association analysis, we utilized additional clinical disorder features and intermediate phenotypes – endophenotypes - in addition to diagnostic information from altogether 290 neuropsychologically assessed schizophrenia families. An intragenic short tandem repeat allele of the regional RELN gene, supposed to play a role in the background of several neurodevelopmental disorders, showed significant association with poorer cognitive functioning and more severe schizophrenia symptoms. Additionally, this risk allele was significantly more prevalent among the individuals affected with schizophrenia spectrum disorders. We have previously identified linkage of schizophrenia and its cognitive endophenotypes on the long arms of chromosomes 2, 4, and 5. In the last part of this study, we selected altogether 104 functionally relevant candidate genes from the linked regions. We detected several promising associations, of which especially interesting are the ERBB4 gene, showing association with the severity of schizophrenia symptoms and impairments in traits related to verbal abilities, and the GRIA1 gene, showing association with the severity of schizophrenia symptoms. Our results extend the previous evidence that the genetic risk for schizophrenia is at least partially mediated via the effects of the candidate genes and their combinations on relevant brain systems, resulting in alterations in different disorder domains, such as the cognitive deficits.

α-Synuclein pathology in very elderly Finns : A population-based clinico-neuropathologic and molecular genetic study of Dementia with Lewy bodies

Populations in developed countries are ageing fast. The elderly have the greatest incidence of de-mentia, and thus the increase in the number of demented individuals, increases the immediate costs for the governments concerning healthcare and hospital treatment. Attention is being paid to disorders behind cognitive impairment with behavioural and psychological symptoms, which are enormous contributors to the hospital care required for the elderly. The highest dreams are in prevention; however, before discovering the tools for preventing dementia, the pathogenesis behind dementia disorders needs to be understood. Dementia with Lewy bodies (DLB), a relatively recently discovered dementia disorder compared to Alzheimer’s disease (AD), is estimated to account for up to one third of primary degenerative dementia, thus being the second most common cause of dementia in the elderly. Nevertheless, the impact of neuropathological and genetic findings on the clinical syndrome of DLB is not fully established. In this present series of studies, the frequency of neuropathological findings of DLB and its relation to the clinical findings was evaluated in a cohort of subjects with primary degenerative dementia and in a population-based prospective cohort study of individuals aged 85 years or older. α-synuclein (αS) immunoreactive pathology classifiable according to the DLB consensus criteria was found in one fourth of the primary degenerative dementia subjects. In the population-based study, the corresponding figure was one third of the population, 38% of the demented and one fifth of the non-demented very elderly Finns. However, in spite of the frequent discovery of αS pathology, its association with the clinical symptoms was quite poor. Indeed, the common clinical features of DLB, hypokinesia and visual hallucinations, associated better with the severe neurofibrillary AD-type pathology than with the extensive (diffuse neocortical) αS pathology when both types of pathology were taken into account. The severity of the neurofibrillary AD-type pathology (Braak stage) associated with the extent of αS pathology in the brain. In addition, the genetic study showed an interaction between tau and αS; common variation in the αS gene (SNCA) associated significantly with the severity of the neurofibrillary AD-type pathology and nominally significantly with the extensive αS pathology. Further, the relevance and temporal course of the substantia nigra (SN) degeneration and of the spinal cord αS pathology were studied in relation to αS pathology in the brain. The linear association between the extent of αS pathology in the brain and the neuron loss in SN suggests that in DLB the degeneration of SN proceeds as the αS pathology extends from SN to the neocortex instead of early destruction of SN seen in Parkinson’s disease (PD). Furthermore, the extent of αS pathology in the brain associated with the severity of αS pathology in the thoracic and sacral autonomic nuclei of the spinal cord. The thoracic αS pathology was more common and more severe compared to sacral cord, suggesting that the progress of αS pathology proceeds downwards from the brainstem towards the sacral spinal cord.

Molecular and clinical characteristics of tricarboxylic acid cycle-associated tumors

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare, dominantly inherited tumor predisposition syndrome characterized by benign cutaneous and uterine (ULM) leiomyomas, and sometimes renal cell cancer (RCC). A few cases of uterine leiomyosarcoma (ULMS) have also been reported. Mutations in a nuclear gene encoding fumarate hydratase (FH), an enzyme of the mitochondrial tricarboxylic acid cycle (TCA cycle), underlie HLRCC. As a recessive condition, germline mutations in FH predispose to a neurological defect, FH deficiency (FHD). Hereditary paragangliomatosis (HPGL) is a dominant disorder associated with paragangliomas and pheochromocytomas. Inherited mutations in three genes encoding subunits of succinate dehydrogenase (SDH), also a TCA cycle enzyme, predispose to HPGL. Both FH and SDH seem to act as tumor suppressors. One of the consequences of the TCA cycle defect is abnormal activation of HIF1 pathway ( pseudohypoxia ) in the HLRCC and HPGL tumors. HIF1 drives transcription of genes encoding e.g. angiogenetic factors which can facilitate tumor growth. Recently hypoxia/HIF1 has been suggested to be one of the causes of genetic instability as well. One of the aims of this study was to broaden the clinical definers of HLRCC. To determine the cancer risk and to identify possible novel tumor types associated with FH mutations eight Finnish HLRCC/FHD families were extensively evaluated. The extension of the pedigrees and the Finnish Cancer Registry based tumor search yielded genealogical and cancer data of altogether 868 individuals. The standardized incidence ratio-based comparison of HLRCC/FHD family members with general Finnish population revealed 6.5-fold risk for RCC. Moreover, risk for ULMS was highly increased. However, according to the recent and more stringent diagnosis criteria of ULMS many of the HLRCC uterine tumors previously considered malignant are at present diagnosed as atypical or proliferative ULMs (with a low risk of recurrence). Thus, the formation of ULMS (as presently defined) in HLRCC appears to be uncommon. Though increased incidence was not observed, interestingly the genetic analyses suggested possible association of breast and bladder cancer with loss of FH. Moreover, cancer cases were exceptionally detected in an FHD family. Another clinical finding was the conventional (clear cell) type RCC of a young Spanish HLRCC patient. Conventional RCC is distinct from the types previously observed in this syndrome but according to these results, FH mutation may underlie some of young conventional cancer cases. Secondly, the molecular pathway from defective TCA cycle to tumor formation was intended to clarify. Since HLRCC and HPGL tumors display abnormally activated HIF1, the hypothesis on the link between HIF1/hypoxia and genetic instability was of interest to study in HLRCC and HPGL tumor material. HIF1α (a subunit of HIF1) stabilization was confirmed in the majority of the specimens. However, no repression of MSH2, a protein of DNA mismatch repair system, or microsatellite instability (MSI), an indicator of genetic instability, was observed. Accordingly, increased instability seems not to play a role in the tumorigenesis of pseudohypoxic TCA cycle-deficient tumors. Additionally, to study the putative alternative functions of FH, a recently identified alternative FH transcript (FHv) was characterized. FHv was found to contain instead of exon 1, an alternative exon 1b. Differential subcellular distribution, lack of FH enzyme activity, low mRNA expression compared to FH, and induction by cellular stress suggest FHv to have a role distinct from FH, for example in apoptosis or survival. However, the physiological significance of FHv requires further elucidation.

Genetic Heterogeneity in Autism Spectrum Disorders in a Population Isolate

Positional cloning has enabled hypothesis-free, genome-wide scans for genetic factors contributing to disorders or traits. Traditionally linkage analysis has been used to identify regions of interest, followed by meticulous fine mapping and candidate gene screening using association methods and finally sequencing of regions of interest. More recently, genome-wide association analysis has enabled a more direct approach to identify specific genetic variants explaining a part of the variance of the phenotype of interest. Autism spectrum disorders (ASDs) are a group of childhood onset neuropsychiatric disorders with shared core symptoms but varying severity. Although a strong genetic component has been established in ASDs, genetic susceptibility factors have largely eluded characterization. Here, we have utilized modern molecular genetic methods combined with the advantages provided by the special population structure in Finland to identify genetic risk factors for ASDs. The results of this study show that numerous genetic risk factors exist for ASDs even within a population isolate. Stratification based on clinical phenotype resulted in encouraging results, as previously identified linkage to 3p14-p24 was replicated in an independent family set of families with Asperger syndrome, but no other ASDs. Fine-mapping of the previously identified linkage peak for ASDs at 3q25-q27 revealed association between autism and a subunit of the 5-hydroxytryptamine receptor 3C (HTR3C). We also used dense, genome-wide single nucleotide polymorphism (SNP) data to characterize the population structure of Finns. We observed significant population substructure which correlates with the known history of multiple consecutive bottle-necks experienced by the Finnish population. We used this information to ascertain a genetically homogenous subset of autism families to identify possible rare, enriched risk variants using genome-wide SNP data. No rare enriched genetic risk factors were identified in this dataset, although a subset of families could be genealogically linked to form two extended pedigrees. The lack of founder mutations in this isolated population suggests that the majority of genetic risk factors are rare, de novo mutations unique to individual nuclear families. The results of this study are consistent with others in the field. The underlying genetic architecture for this group of disorders appears highly heterogeneous, with common variants accounting for only a subset of genetic risk. The majority of identified risk factors have turned out to be exceedingly rare, and only explain a subset of the genetic risk in the general population in spite of their high penetrance within individual families. The results of this study, together with other results obtained in this field, indicate that family specific linkage, homozygosity mapping and resequencing efforts are needed to identify these rare genetic risk factors.

Helicobacter pylori in Vammala, Finland: seroepidemiological studies and a population-based ‘screen-and-treat’ programme

Helicobacter pylorin (helikobakteeri) tartunta saadaan yleensä lapsena ja tauti jää tavallisesti pysyväksi ilman täsmähoitoa. Onnistunut hoito parantaa pysyvästi helikobakteerista aiheutuvan mahan haavataudin ja näyttää ehkäisevän mahalaukun pahanlaatuisten muutosten kehittymistä. Aloitimme Vammalassa terveyskeskuksessa toteutetun kansainvälisesti ainutlaatuisen väestöpohjaisen helikobakteeritulehduksen seulonta- ja hoito-ohjelman pilottitutkimuksella 1994. 1996 kaikki 15-40-vuotiaat ja 1997-2000 15- ja 45-vuotiaat vammalalaiset kutsuttiin verinäyteseulontaan. Yhteensä 4626 henkilöä (75% kutsutuista) osallistui seulontaan. Vasta-ainepositiivisille tarjottiin helikobakteeritulehduksen lopettava lääkekuuri. Toiminnan seurauksena helikobakteeritulehduksen esiintyvyyden laskettiin vähentyneen 12%:sta 4%:iin 15-40-vuotiaiden ikäryhmässä. Tutkimme myös helikobakteerivasta-ainepositiivisten ja -negatiivisten eroja sekä helikobakteeritulehduksen riskitekijöitä kyselytutkimuksella. Lapsuudenkodin asumisahtauden, äidin matalan koulutusasteen, tupakoinnin, alkoholinkäytön, huonojen asunto-olojen ja ylävatsavaivoista johtuvien sairauslomien todettiin liittyvän helikobakteeritulehdukseen monimuuttuja-analyysissa. Tutkimme seulontaohjelmassa käyttämiemme IgG- ja IgA-luokan helikobakteeri-vasta-ainetestien luotettavuutta eri ikäryhmissä ottaen huomioon atrofisen gastriitin esiintyvyyden. 561 kliinisin perustein gastroskopoidun potilaan aineistossa IgG-testi osoittautui erittäin herkäksi kaikissa ikäryhmissä (99%). Tarkkuus oli myös vanhemmissa ikäryhmissä hyvä (97-93%), kun atrofista gastriittia sairastavat suljettiin pois. IgA- ja CagA-helikobakteerivasta-aineiden on todettu liittyvän lisääntyneeseen mahahaava- ja mahasyöpäriskiin. Analysoimme 560 henkilön pariseeruminäytteet, jotka oli otettu kahden vuosikymmenen välein, ja totesimme, että IgA-vasta-aineiden esiintyvyyden lisääntyyminen iän myötä johtuu paitsi syntymäajankohdasta ja uusista infektioista myös IgA-vasta-ainetasojen kohoamisesta helikobakteeritulehduksen aikana. Selvitimme myös CagA-vasta-ainetasojen muuttumista analysoimalla seeruminäytteet, jotka oli otettu kahden vuosikymmenen välein. Totesimme, että samanaikaisesti kun helikobakteerin esiintyvyys väestössä on alentunut, erityisesti CagA-positiiviset infektiot ovat vähentyneet. Tutkimuksemme osoittaa, että Suomessa terveyskeskuksen yhteydessä voidaan toteuttaa näin laajamittainen seulonta- ja hoito-ohjelma, johon suomalaiset osallistuvat aktiivisesti. Nähtäväksi jää, kuinka paljon ohjelma kykeni vähentämään helikobakteeritulehdukseen liittyviä myöhäisseuraamuksia.

Risk factors for open angle glaucoma; a clinical and molecular genetic study

Glaucoma, optic neuropathy with excavation in the optic nerve head and corresponding visual field defect, is one of the leading causes for blindness worldwide. However, visual disability can often be avoided or delayed if the disease is diagnosed at an early stage. Therefore, recognising the risk factors for development and progression of glaucoma may prevent further damage. The purpose of the present study was to evaluate factors associated with visual disability caused by glaucoma and the genetic features of two risk factors, exfoliation syndrome (ES) and a positive family history of glaucoma. The present study material consisted of three study groups 1) deceased glaucoma patients from the Ekenäs practice 2) glaucoma families from the Ekenäs region and 3) population based families with and without exfoliation syndrome from Kökar Island. For the retrospective study, 106 patients with open angle glaucoma (OAG) were identified. At the last visit, 17 patients were visually impaired. Blindness induced by glaucoma was found in one or both eyes in 16 patients and in both eyes in six patients. The cumulative incidence of glaucoma caused blindness for one eye was 6% at 5 years, 9% at 10 years, and 15% at 15 years from initialising the treatment. The factors associated with blindness caused by glaucoma were an advanced stage of glaucoma at diagnosis, fluctuation in intraocular pressure during treatment, the presence of exfoliation syndrome, and poor patient compliance. A cross-sectional population based study performed in 1960-1962 on Kökar Island and the same population was followed until 2002. In total 965 subjects (530 over 50 years) have been examined at least once. The prevalence of exfoliation syndrome (ES) was 18% among subjects older than 50 years. Seventy-five of all 78 ES-positives belonged to the same extended pedigree. According to the segregation and family analysis, exfoliation syndrome seemed to be inherited as an autosomal dominant trait with reduced penetrance. The penetrance was more reduced for males, but the risk for glaucoma was higher in males than in females. To find the gene or genes associated with exfoliation syndrome, a genome wide scan was performed for 64 members (28 ES affected and 36 controls) of the Kökar pedigree. A promising result was found: the highest two-point LOD score of 3.45 (θ=0.04) in chromosome18q12.1-21.33. The presence of mutations in glaucoma genes TIGR/MYOC (myocilin) and OPTN (optineurin) was analysed in eight glaucoma families from the Ekenäs region. An inheritance pattern resembling autosomal dominant mode was detected in all these families. Primary open angle glaucoma or exfoliation glaucoma was found in 35% of 136 family members and 28% were suspected to have glaucoma. No mutations were detected in these families.

Long-term clinical outcome after liver transplantation

With transplant rejection rendered a minor concern and survival rates after liver transplantation (LT) steadily improving, long-term complications are attracting more attention. Current immunosuppressive therapies, together with other factors, are accompanied by considerable long-term toxicity, which clinically manifests as renal dysfunction, high risk for cardiovascular disease, and cancer. This thesis investigates the incidence, causes, and risk factors for such renal dysfunction, cardiovascular risk, and cancer after LT. Long-term effects of LT are further addressed by surveying the quality of life and employment status of LT recipients. The consecutive patients included had undergone LT at Helsinki University Hospital from 1982 onwards. Data regarding renal function – creatinine and estimated glomerular filtration rate (GFR) – were recorded before and repeatedly after LT in 396 patients. The presence of hypertension, dyslipidemia, diabetes, impaired fasting glucose, and overweight/obesity before and 5 years after LT was determined among 77 patients transplanted for acute liver failure. The entire cohort of LT patients (540 patients), including both children and adults, was linked with the Finnish Cancer Registry, and numbers of cancers observed were compared to site-specific expected numbers based on national cancer incidence rates stratified by age, gender, and calendar time. Health-related quality of life (HRQoL), measured by the 15D instrument, and employment status were surveyed among all adult patients alive in 2007 (401 patients). The response rate was 89%. Posttransplant cardiovascular risk factor prevalence and HRQoL were compared with that in the age- and gender-matched Finnish general population. The cumulative risk for chronic kidney disease increased from 10% at 5 years to 16% at 10 years following LT. GFR up to 10 years after LT could be predicted by the GFR at 1 year. In patients transplanted for chronic liver disease, a moderate correlation of pretransplant GFR with later GFR was also evident, whereas in acute liver failure patients after LT, even severe pretransplant renal dysfunction often recovered. By 5 years after LT, 71% of acute liver failure patients were receiving antihypertensive medications, 61% were exhibiting dyslipidemia, 10% were diabetic, 32% were overweight, and 13% obese. Compared with the general population, only hypertension displayed a significantly elevated prevalence among patients – 2.7-fold – whereas patients exhibited 30% less dyslipidemia and 71% less impaired fasting glucose. The cumulative incidence of cancer was 5% at 5 years and 13% at 10. Compared with the general population, patients were subject to a 2.6-fold cancer risk, with non-melanoma skin cancer (standardized incidence ratio, SIR, 38.5) and non-Hodgkin lymphoma (SIR 13.9) being the predominant malignancies. Non-Hodgkin lymphoma was associated with male gender, young age, and the immediate posttransplant period, whereas old age and antibody induction therapy raised skin-cancer risk. HRQoL deviated clinically unimportantly from the values in the general population, but significant deficits among patients were evident in some physical domains. HRQoL did not seem to decrease with longer follow-up. Although 87% of patients reported improved working capacity, data on return to working life showed marked age-dependency: Among patients aged less than 40 at LT, 70 to 80% returned to work, among those aged 40 to 50, 55%, and among those above 50, 15% to 28%. The most common cause for unemployment was early retirement before LT. Those patients employed exhibited better HRQoL than those unemployed. In conclusion, although renal impairment, hypertension, and cancer are evidently common after LT and increase with time, patients’ quality of life remains comparable with that of the general population.

Assessment of neuroleptic-induced movement disorders in a naturalistic schizophrenia population

The prevalence and assessment of neuroleptic-induced movement disorders (NIMDs) in a naturalistic schizophrenia population that uses conventional neuroleptics were studied. We recruited 99 chronic schizophrenic institutionalized adult patients from a state nursing home in central Estonia. The total prevalence of NIMDs according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) was 61.6%, and 22.2% had more than one NIMD. We explored the reliability and validity of different instruments for measuring these disorders. First, we compared DSM-IV with the established observer rating scales of Barnes Akathisia Rating Scale (BARS), Simpson-Angus Scale (SAS) (for neuroleptic-induced parkinsonism, NIP) and Abnormal Involuntary Movement Scale (AIMS) (for tardive dyskinesia), all three of which have been used for diagnosing NIMD. We found a good overlap of cases for neuroleptic-induced akathisia (NIA) and tardive dyskinesia (TD) but somewhat poorer overlap for NIP, for which we suggest raising the commonly used threshold value of 0.3 to 0.65. Second, we compared the established observer rating scales with an objective motor measurement, namely controlled rest lower limb activity measured by actometry. Actometry supported the validity of BARS and SAS, but it could not be used alone in this naturalistic population with several co-existing NIMDs. It could not differentiate the disorders from each other. Quantitative actometry may be useful in measuring changes in NIA and NIP severity, in situations where the diagnosis has been made using another method. Third, after the relative failure of quantitative actometry to show diagnostic power in a naturalistic population, we explored descriptive ways of analysing actometric data, and demonstrated diagnostic power pooled NIA and pseudoakathisia (PsA) in our population. A subjective question concerning movement problems was able to discriminate NIA patients from all other subjects. Answers to this question were not selective for other NIMDs. Chronic schizophrenia populations are common worldwide, NIMD affected two-thirds of our study population. Prevention, diagnosis and treatment of NIMDs warrant more attention, especially in countries where typical antipsychotics are frequently used. Our study supported the validity and reliability of DSM-IV diagnostic criteria for NIMD in comparison with established rating scales and actometry. SAS can be used with minor modifications for screening purposes. Controlled rest lower limb actometry was not diagnostically specific in our naturalistic population with several co-morbid NIMDs, but it may be sensitive in measuring changes in NIMDs.

Ballistic Trauma in Finland : An Epidemiologic and Clinical Study of Firearm and Explosion Injuries

The occurrence and nature of civilian firearm- and explosion-injuries in Finland, and the nature of severe gunshot injuries of the extremities were described in seven original articles. The main data sources used were the National Hospital Discharge Register, the Cause-of-Death Register, and the Archive of Death Certificates at Statistics Finland. The present study was population based. Epidemiologic methods were used in six and clinical analyses in five papers. In these clinical studies, every original hospital record and death certificate was critically analyzed. The trend of hospitalized firearm injuries has slightly declined in Finland from the late 1980s to the early 2000s. The occurrence decreased from 5.1 per 100 000 person-years in 1990 to 2.6 in 2003. The decline was found in the unintentional firearm injuries. A high incidence of unintentional injuries by firearms was characteristic of the country, while violence and homicides by firearms represented a minor problem. The incidence of fatal non-suicidal firearm injuries has been stable, 1.8 cases per 100 000 person-years. Suicides using firearms were eight times more common during the period studied. This is contrary to corresponding reports from many other countries. However, the use of alcohol and illegal drugs or substances was detected in as many as one-third of the injuries studied. The median length of hospitalization was three days and it was significantly associated (p<0.001) with the type of injury. The mean length of hospital stay has decreased from the 1980s to the early 2000s. In this study, there was a special interest in gunshot injuries of the extremities. From a clinical point of view, the nature of severe extremital gunshot wounds, as well as the primary operative approach in their management, varied. The patients with severe injuries of this kind were managed at university and central hospital emergency departments, by general surgeons in smaller hospitals and by cardiothoracic or vascular surgeons in larger hospitals. Injuries were rarities and as such challenges for surgeons on call. Some noteworthy aspects of the management were noticed and these should be focused on in the future. On the other hand, the small population density and the relatively large geographic area of Finland do not favor high volume, centralized trauma management systems. However, experimental war surgery has been increasingly taught in the country from the 1990s, and excellent results could be expected during the present decade. Epidemiologically, explosion injuries can be considered a minor problem in Finland at present, but their significance should not be underestimated. Fatal explosion injuries showed up sporadically. An increase occurred from 2002 to 2004 for no obvius reason. However, in view of the historical facts, a possibility for another rare major explosion involving several people might become likely within the next decade. The national control system of firearms is mainly based on the new legislations from 1998 and 2002. However, as shown in this study, there is no reason to assume that the national hospitalization policies, or the political climate, or the legislation might have changed over the study period and influenced the declining development, at least not directly. Indeed, the reason for the decline to appear in the incidence of unintentional injuries only remains unclear. It may derive from many practical steps, e.g. locked firearm cases, or from the stability of the community itself. For effective reduction of firearm-related injuries, preventive measures, such as education and counseling, should be targeted at recreational firearm users. To sum up, this study showed that the often reported increasing trend in firearm as well as explosion-related injuries has not manifested in Finland. Consequently, it can be recognized that, overall, the Finnish legislation together with the various strategies have succeeded in preventing firearm- and explosion-related injuries in the country.

Randomised Evaluation of New Technologies within the Population‐Based Cervical Cancer Screening Programme in Finland: Cross‐Sectional Performance and Validity

A randomised and population-based screening design with new technologies has been applied to the organised cervical cancer screening programme in Finland. In this experiment the women invited to routine five-yearly screening are individually randomised to be screened with automation-assisted cytology, human papillomavirus (HPV) test or conventional cytology. By using the randomised design, the ultimate aim is to assess and compare the long-term outcomes of the different screening regimens. The primary aim of the current study was to evaluate, based on the material collected during the implementation phase of the Finnish randomised screening experiment, the cross-sectional performance and validity of automation-assisted cytology (Papnet system) and primary HPV DNA testing (Hybrid Capture II assay for 13 oncogenic HPV types) within service screening, in comparison to conventional cytology. The parameters of interest were test positivity rate, histological detection rate, relative sensitivity, relative specificity and positive predictive value. Also, the effect of variation in performance by screening laboratory on age-adjusted cervical cancer incidence was assessed. Based on the cross-sectional results, almost no differences were observed in the performance of conventional and automation-assisted screening. Instead, primary HPV screening found 58% (95% confidence interval 19-109%) more cervical lesions than conventional screening. However, this was mainly due to overrepresentation of mild- and moderate-grade lesions and, thus, is likely to result in overtreatment since a great deal of these lesions would never progress to invasive cancer. Primary screening with an HPV DNA test alone caused substantial loss in specificity in comparison to cytological screening. With the use of cytology triage test, the specificity of HPV screening improved close to the level of conventional cytology. The specificity of primary HPV screening was also increased by increasing the test positivity cutoff from the level recommended for clinical use, but the increase was more modest than the one gained with the use of cytology triage. The performance of the cervical cancer screening programme varied widely between the screening laboratories, but the variation in overall programme effectiveness between respective populations was more marginal from the very beginning of the organised screening activity. Thus, conclusive interpretations on the quality or success of screening should not be based on performance parameters only. In the evaluation of cervical cancer screening the outcome should be selected as closely as possible to the true measure of programme effectiveness, which is the number of invasive cervical cancers and subsequent deaths prevented in the target population. The evaluation of benefits and adverse effects of each new suggested screening technology should be performed before the technology becomes an accepted routine in the existing screening programme. At best, the evaluation is performed randomised, within the population and screening programme in question, which makes the results directly applicable to routine use.

Spirometric studies on the adult general population of Helsinki : bronchodilation responses, determinants, and intrasession repeatability of FEV1, FEV6, FVC, and forced expiratory time

Spirometry is the most widely used lung function test in the world. It is fundamental in diagnostic and functional evaluation of various pulmonary diseases. In the studies described in this thesis, the spirometric assessment of reversibility of bronchial obstruction, its determinants, and variation features are described in a general population sample from Helsinki, Finland. This study is a part of the FinEsS study, which is a collaborative study of clinical epidemiology of respiratory health between Finland (Fin), Estonia (Es), and Sweden (S). Asthma and chronic obstructive pulmonary disease (COPD) constitute the two major obstructive airways diseases. The prevalence of asthma has increased, with around 6% of the population in Helsinki reporting physician-diagnosed asthma. The main cause of COPD is smoking with changes in smoking habits in the population affecting its prevalence with a delay. Whereas airway obstruction in asthma is by definition reversible, COPD is characterized by fixed obstruction. Cough and sputum production, the first symptoms of COPD, are often misinterpreted for smokers cough and not recognized as first signs of a chronic illness. Therefore COPD is widely underdiagnosed. More extensive use of spirometry in primary care is advocated to focus smoking cessation interventions on populations at risk. The use of forced expiratory volume in six seconds (FEV6) instead of forced vital capacity (FVC) has been suggested to enable office spirometry to be used in earlier detection of airflow limitation. Despite being a widely accepted standard method of assessment of lung function, the methodology and interpretation of spirometry are constantly developing. In 2005, the ATS/ERS Task Force issued a joint statement which endorsed the 12% and 200 ml thresholds for significant change in forced expiratory volume in one second (FEV1) or FVC during bronchodilation testing, but included the notion that in cases where only FVC improves it should be verified that this is not caused by a longer exhalation time in post-bronchodilator spirometry. This elicited new interest in the assessment of forced expiratory time (FET), a spirometric variable not usually reported or used in assessment. In this population sample, we examined FET and found it to be on average 10.7 (SD 4.3) s and to increase with ageing and airflow limitation in spirometry. The intrasession repeatability of FET was the poorest of the spirometric variables assessed. Based on the intrasession repeatability, a limit for significant change of 3 s was suggested for FET during bronchodilation testing. FEV6 was found to perform equally well as FVC in the population and in a subgroup of subjects with airways obstruction. In the bronchodilation test, decreases were frequently observed in FEV1 and particularly in FVC. The limit of significant increase based on the 95th percentile of the population sample was 9% for FEV1 and 6% for FEV6 and FVC; these are slightly lower than the current limits for single bronchodilation tests (ATS/ERS guidelines). FEV6 was proven as a valid alternative to FVC also in the bronchodilation test and would remove the need to control duration of exhalation during the spirometric bronchodilation test.

Reduced visual function and its association with physical functioning in the Finnish adult population : Prevalence, causes, and need for eye care services

The purpose of this study was to estimate the prevalence and distribution of reduced visual acuity, major chronic eye diseases, and subsequent need for eye care services in the Finnish adult population comprising persons aged 30 years and older. In addition, we analyzed the effect of decreased vision on functioning and need for assistance using the World Health Organization’s (WHO) International Classification of Functioning, Disability, and Health (ICF) as a framework. The study was based on the Health 2000 health examination survey, a nationally representative population-based comprehensive survey of health and functional capacity carried out in 2000 to 2001 in Finland. The study sample representing the Finnish population aged 30 years and older was drawn by a two-stage stratified cluster sampling. The Health 2000 survey included a home interview and a comprehensive health examination conducted at a nearby screening center. If the invited participants did not attend, an abridged examination was conducted at home or in an institution. Based on our finding in participants, the great majority (96%) of Finnish adults had at least moderate visual acuity (VA ≥ 0.5) with current refraction correction, if any. However, in the age group 75–84 years the prevalence decreased to 81%, and after 85 years to 46%. In the population aged 30 years and older, the prevalence of habitual visual impairment (VA ≤ 0.25) was 1.6%, and 0.5% were blind (VA < 0.1). The prevalence of visual impairment increased significantly with age (p < 0.001), and after the age of 65 years the increase was sharp. Visual impairment was equally common for both sexes (OR 1.20, 95% CI 0.82 – 1.74). Based on self-reported and/or register-based data, the estimated total prevalences of cataract, glaucoma, age-related maculopathy (ARM), and diabetic retinopathy (DR) in the study population were 10%, 5%, 4%, and 1%, respectively. The prevalence of all of these chronic eye diseases increased with age (p < 0.001). Cataract and glaucoma were more common in women than in men (OR 1.55, 95% CI 1.26 – 1.91 and OR 1.57, 95% CI 1.24 – 1.98, respectively). The most prevalent eye diseases in people with visual impairment (VA ≤ 0.25) were ARM (37%), unoperated cataract (27%), glaucoma (22%), and DR (7%). One-half (58%) of visually impaired people had had a vision examination during the past five years, and 79% had received some vision rehabilitation services, mainly in the form of spectacles (70%). Only one-third (31%) had received formal low vision rehabilitation (i.e., fitting of low vision aids, receiving patient education, training for orientation and mobility, training for activities of daily living (ADL), or consultation with a social worker). People with low vision (VA 0.1 – 0.25) were less likely to have received formal low vision rehabilitation, magnifying glasses, or other low vision aids than blind people (VA < 0.1). Furthermore, low cognitive capacity and living in an institution were associated with limited use of vision rehabilitation services. Of the visually impaired living in the community, 71% reported a need for assistance and 24% had an unmet need for assistance in everyday activities. Prevalence of ADL, instrumental activities of daily living (IADL), and mobility increased with decreasing VA (p < 0.001). Visually impaired persons (VA ≤ 0.25) were four times more likely to have ADL disabilities than those with good VA (VA ≥ 0.8) after adjustment for sociodemographic and behavioral factors and chronic conditions (OR 4.36, 95% CI 2.44 – 7.78). Limitations in IADL and measured mobility were five times as likely (OR 4.82, 95% CI 2.38 – 9.76 and OR 5.37, 95% CI 2.44 – 7.78, respectively) and self-reported mobility limitations were three times as likely (OR 3.07, 95% CI 1.67 – 9.63) as in persons with good VA. The high prevalence of age-related eye diseases and subsequent visual impairment in the fastest growing segment of the population will result in a substantial increase in the demand for eye care services in the future. Many of the visually impaired, especially older persons with decreased cognitive capacity or living in an institution, have not had a recent vision examination and lack adequate low vision rehabilitation. This highlights the need for regular evaluation of visual function in the elderly and an active dissemination of information about rehabilitation services. Decreased VA is strongly associated with functional limitations, and even a slight decrease in VA was found to be associated with limited functioning. Thus, continuous efforts are needed to identify and treat eye diseases to maintain patients’ quality of life and to alleviate the social and economic burden of serious eye diseases.