Study of sleep and evaluation of sumatriptan and rizatriptan in the acute treatment of migraine in children and adolescents

Migraine is a common disease in children and adolescents, affecting roughly 10% of school-aged children. Recent studies have revealed an increasing incidence of childhood migraine, but migraine remains an underrecognized and undertreated condition in the pediatric population. Migraine attacks are painful and disabling and can affect a child´s life in many ways. Effective drug treatment is usually needed. The new migraine drugs, triptans, were introduced at the beginning of the 1990s and have since been shown to be very effective in the treatment of migraine attacks in adults. Although they are widely used in adults, the acute treatment of migraine in children and adolescents is still based on paracetamol and nonsteroidal anti-inflammatory drugs. Some children can control their attacks satisfactorily with simple analgesics, but at least one-third need more powerful treatments. When this thesis work commenced, hardly any information existed on the efficacy and safety of triptans in children. The study aim of the thesis was to identify more efficient treatments of migraine for children and adolescents by investigating the efficacy of sumatriptan nasal spray and oral rizatriptan compared with placebo in them. Sleep has an impact on migraine in many aspects. Despite the clinical relevance and common manifestation of sleep in the context of migraine in children, very little research data on the true frequency of sleep exist. As sleeping is so often related to childhood migraine, it can be a confounding factor in clinical drug trials of migraine treatments in children and adolescents. How the results of a sleeping child should be analyzed is under continual debate. The aim of the thesis was also to clarify this as well as to evaluate the frequency of sleeping during migraine attacks in children and factors affecting frequency. Both nasal sumatriptan and oral rizatriptan were effective (superior to placebo), and well tolerated in treatment of migraine attacks in children and adolescents aged 8-17 and 6-17 years, respectively. No serous adverse effects were observed. The results of this work suggest that nasal sumatriptan 20 mg and rizatriptan 10 mg can be effectively and safely used to treat migraine attacks in adolescents aged over 12 years if more effective drugs than NSAIDs are needed. No difference was observed in efficacy or safety of nasal sumatriptan and rizatriptan between children aged younger than 12 years and older children, but because the treated number of patients under 12 years is still small, more studies are needed before sumatriptan or rizatriptan can be recommended for use in this population. Sleeping during migraine attacks was very common, and most children at least occasionally slept during an attack. Falling asleep was especially common in children under eight years of age and during the first hour after the onset of attack. Children who were able to sleep soon after attack onset were more likely pain-free at two hours. Sleeping probably both improves recovery from a migraine attack and is a sign of headache relief. Falling asleep should be classified as a sign of headache relief in clinical drug trials when studying migraine treatments in children and adolescents.

Children and adolescents in full-time special education : an epidemiological and magnetic resonance imaging study

The need for special education (SE) is increasing. The majority of those whose problems are due to neurodevelopmental disorders have no specific aetiology. The aim of this study was to evaluate the contribution of prenatal and perinatal factors and factors associated with growth and development to later need for full-time SE and to assess joint structural and volumetric brain alterations among subjects with unexplained, familial need for SE. A random sample of 900 subjects in full-time SE allocated into three levels of neurodevelopmental problems and 301 controls in mainstream education (ME) provided data on socioeconomic factors, pregnancy, delivery, growth, and development. Of those, 119 subjects belonging to a sibling-pair in full-time SE with unexplained aetiology and 43 controls in ME underwent brain magnetic resonance imaging (MRI). Analyses of structural brain alterations and midsagittal area and diameter measurements were made. Voxel-based morphometry (VBM) analysis provided detailed information on regional grey matter, white matter, and cerebrospinal fluid (CSF) volume differences. Father’s age ≥ 40 years, low birth weight, male sex, and lower socio-economic status all increased the probability of SE placement. At age 1 year, one standard deviation score decrease in height raised the probability of SE placement by 40% and in head circumference by 28%. At infancy, the gross motor milestones differentiated the children. From age 18 months, the fine motor milestones and those related to speech and social skills became more important. Brain MRI revealed no specific aetiology for subjects in SE. However, they had more often ≥ 3 abnormal findings in MRIs (thin corpus callosum and enlarged cerebral and cerebellar CSF spaces). In VBM, subjects in full-time SE had smaller global white matter, CSF, and total brain volumes than controls. Compared with controls, subjects with intellectual disabilities had regional volume alterations (greater grey matter volumes in the anterior cingulate cortex bilaterally, smaller grey matter volume in left thalamus and left cerebellar hemisphere, greater white matter volume in the left fronto-parietal region, and smaller white matter volumes bilaterally in the posterior limbs of the internal capsules). In conclusion, the epidemiological studies emphasized several factors that increased the probability of SE placement, useful as a framework for interventional studies. The global and regional brain MRI findings provide an interesting basis for future investigations of learning-related brain structures in young subjects with cognitive impairments or intellectual disabilities of unexplained, familial aetiology.

Bone Health in Children and Adolescents with Juvenile Idiopathic Arthritis and Solid Organ Transplant

Osteoporosis is a skeletal disorder characterized by compromised bone strength that predisposes to increased fracture risk. Childhood and adolescence are critical periods for bone mass gain. Peak bone mass is mostly acquired by the age of 18 years and is an important determinant of adult bone health and lifetime risk for fractures. Medications, especially glucocorticoids (GCs), chronic inflammation, decreased physical activity, hormonal deficiencies, delayed puberty, and poor nutrition may predispose children and adolescents with a chronic disease to impaired bone health. In this work, we studied overall bone health, the incidence and prevalence of fractures in children and adolescents who were treated for juvenile idiopathic arthritis (JIA) or had undergone solid organ transplantation. The first study cohort included 62 patients diagnosed with JIA and treated with GCs. The epidemiology of fractures after transplantation was investigated in 196 patients and a more detailed analysis of bone health determinants was performed on 40 liver (LTx) and 106 renal (RTx) transplantation patients. Bone mineral density (BMD) and vertebral morphology were assessed by dual-energy x-ray absorptiometry. Standard radiographs were obtained to detect vertebral fractures and to determine bone age; BMD values were adjusted for skeletal maturity. Our study showed that median BMD values were subnormal in all patient cohorts. The values were highest in patients with JIA and lowest in patients with LTx. Age at transplantation influenced BMD values in LTx but not RTx patients; BMD values were higher in patients who had LTx before the age of two years. BMD was lowest during the immediate posttransplantation years and increased subnormally during puberty. Delayed skeletal maturation was common in all patient groups. The prevalence of vertebral fractures ranged from 10% to 19% in the cohorts. Most of the fractures were asymptomatic and diagnosed only at screening. Vertebral fractures were most common in LTx patients. Vitamin D deficiency was common in all patient groups, and only 3% of patients with JIA and 25% of transplantation patients were considered to have adequate serum vitamin D levels. The total cumulative weight-adjusted dose of GC was not associated with BMD values in JIA or LTx patients. The combination of female gender and age over 15 years, parathyroid hormone concentration over 100 ng/L, and cumulative weight-adjusted methylprednisolone dose over 150 mg/kg during the three preceding years were found to be important predictors for low lumbar spine BMD in RTx patients. Based on the high prevalence of osteoporosis in the study cohorts more efforts should be put to prevention and early diagnosis of osteoporosis in these pediatric patients.

Circulating Glucocorticoid Bioactivity and Serum Glucocorticoid-Responsive Biomarkers during Steroid Therapy in Children and Adolescents with Inflammatory Bowel Disease

Objective: Glucocorticoid therapy is used worldwide to treat various inflammatory and immune conditions, including inflammatory bowel disease (IBD). In IBD, 80% of the patients obtain a positive response to the therapy; however the development of glucocorticoid-related side-effects is common. Our aim was therefore to study the possibility of optimizing glucocorticoid therapy in children and adolescents with IBD by measuring circulating glucocorticoid bioactivity (GBA) and serum glucocorticoid-responsive biomarkers in patients receiving steroid treatment for active disease. Methods: A total of sixty-nine paediatric IBD patients from the Paediatric Outpatient Clinics of the University Hospitals of Helsinki and Tampere participated in the studies. Control patients included 101 non-IBD patients and 41 disease controls in remission. In patients with active disease, blood samples were withdrawn before the glucocorticoid therapy was started, at 2-4 weeks after the initiation of the steroid and at 1-month intervals thereafter. Clinical response to glucocorticoid treatment and the development of steroid adverse events was carefully registered. GBA was analyzed with a COS-1 cell bioassay. The measured glucocorticoid therapy-responsive biomarkers included adipocyte-derived adiponectin and leptin, bone turnover-related collagen markers amino-terminal type I procollagen propeptide (PINP) and carboxyterminal telopeptide of type I collagen (ICTP) as well as insulin-like growth factor 1 (IGF-1) and sex hormone-binding globulin (SHBG), and inflammatory marker high-sensitivity C-reactive protein (hs-CRP). Results: The most promising marker for glucocorticoid sensitivity was serum adiponectin that associated with steroid therapy–related adverse events. Serum leptin indicated a similar trend. In contrast, circulating GBA rose in all subjects receiving glucocorticoid treatment but did not associate with the clinical response to steroids or with glucocorticoid therapy-related side-effects. Of notice, young patients (<10 years) showed similar GBA levels than older patients, despite receiving higher weight-adjusted doses of glucocorticoid. Markers of bone formation were lower in children with active IBD than in the control patients, probably reflecting the suppressive effect of the active inflammation. The onset of the glucocorticoid therapy further suppressed bone turnover. Inflammatory marker hs-CRP decreased readily after the initiation of the steroid, however the decrease did not associate with the clinical response to glucocorticoids. Conclusions: This is the first study to show that adipocyte-derived adiponectin associates with steroid therapy-induced side-effects. Further studies are needed, but it is possible that the adiponectin measurement could aid the recognition of glucocorticoid-sensitive patients in the future. GBA and the other markers reflecting glucocorticoid activity in different tissues changed during the treatment, however their change did not correlate with the therapeutic response to steroids or with the development of glucocorticoid-related side effects and therefore cannot guide the therapy in these patients. Studies such as as the present one that combine clinical data with newly developed biomolecular technology are needed to step-by-step build a general picture of the glucocorticoid actions in different tissues.

Growing Up Vietnamese in Finland - Looking Back 12 Years Later : The Well-Being and Sociocultural Adaptation of Vietnamese as Children or Adolescents and as Young Adults

Varttuminen vietnamilaisena Suomessa: 12 vuoden seurantajakso – Vietnamilaisten hyvinvointi ja sosiokulttuurinen sopeutuminen lapsena/nuorena sekä nuorena aikuisena Tämä tutkimus oli määrällinen pitkittäistutkimus lapsena tai nuorena vuosina 1979-1991 Suomeen saapuneiden vietnamilaisten akkulturaatiosta (kulttuurin muutoksista), psyykkisestä hyvinvoinnista ja sosiokulttuurisesta sopeutumisesta. Tutkimukseen osallistui ensimmäisessä vaiheessa (vuonna 1992) 97 satunnaisesti valittua vietnamilaista peruskoululaista ympäri maata, joita verrattin suomalaisiin luokkatovereihin. Seurantavaiheeseen (vuonna 2004) osallistui 59 ensimmäisessä vaiheessa mukana ollutta vietnamilaista, nyt iältään 20 – 31 -vuotiaita. Tutkimuksen tavoitteena oli selvittää mitkä tekijät ennustivat akkulturaation lopputuloksia, samalla huomioiden iän ja ympäristön (kontekstin) vaikutukset psyykkiseen hyvinvointiin ja sosiokulttuuriseen sopeutumiseen. Yksittäiset akkulturaatiodimensiot (kieli, arvot ja identiteetti) osoittautuivat tärkeämmiksi psyykkiselle hyvinvoinnille ja sosiokulttuuriselle sopeutumiselle kuin etniset, kansalliset tai kaksikulttuuriset profiilit, joissa yhdistyivät ao. kieli, arvot ja identiteetti. Identiteettimuutosta tapahtui (etniseen) vietnamilaiseen suuntaan ajan kuluessa, kun taas arvomuutosta tapahtui (kansalliseen) suomalaiseen suuntaan. Sekä suomen että vietnamin kielen taito lisääntyivät ajan myötä, millä oli myönteisiä vaikutuksia sekä psyykkiseen hyvinvointiin että sosiokulttuuriseen sopeutumiseen. Lähtötilanteen psyykkinen hyvinvointi ennusti hyvinvointia (masennuksen puutetta ja itsetuntoa) aikuisena, mutta sosiokulttuurinen sopeutuminen (koulumenestys) lapsena tai nuorena ei ennustanut kouluttautumista aikuisena. Parempi suomen kielen taito ja vähemmän identifioitumista suomalaiseksi aikuisena sekä masentuneisuuden puute ja vähemmän koettua syrjintää lapsena tai nuorena erottelivat psyykkisesti paremmin voivat aikuiset (ei-masentuneet) heistä, jotka olivat masentuneita. Parempaa kouluttautumista aikuisena ennustivat toisaalta vähemmän koettua syrjintää lapsena tai nuorena ja toisaalta aikuisena parempi suomen kielen taito, suurempi kansallisten (suomalaisten) itsenäisyysarvojen kannattaminen, mutta kuitenkin vähemmän identifioitumista suomalaisiin. Koetun syrjinnän merkitys psyykkiselle hyvinvoinnille, erityisesti lapsena tai nuorena, sekä sen pitkäaikaisvaikutukset psyykkiselle hyvinvoinnille ja sosiokulttuuriselle sopeutumiselle aikuisena osoittavat tarpeen puuttua varhain psyykkisiin ongelmiin sekä parantaa etnisten ryhmien välisiä suhteita. Avainsanat: akkulturaatio, psyykkinen hyvinvointi, sosiokultuurinen sopeutuminen, kieli, arvot, identiteetti, vietnamilainen, Suomi, lapset, nuoret, nuoret aikuiset

Assessment of Risk for Type 1 Diabetes in Children of Affected Families and in the General Population : Role of Immunological and Metabolic Markers

Background and aims. Type 1 diabetes (T1D), an autoimmune disease in which the insulin producing beta cells are gradually destroyed, is preceded by a prodromal phase characterized by appearance of diabetes-associated autoantibodies in circulation. Both the timing of the appearance of autoantibodies and their quality have been used in the prediction of T1D among first-degree relatives of diabetic patients (FDRs). So far, no general strategies for identifying individuals at increased disease risk in the general population have been established, although the majority of new cases originate in this population. The current work aimed at assessing the predictive role of diabetes-associated immunologic and metabolic risk factors in the general population, and comparing these factors with data obtained from studies on FDRs. Subjects and methods. Study subjects in the current work were subcohorts of participants of the Childhood Diabetes in Finland Study (DiMe; n=755), the Cardiovascular Risk in Young Finns Study (LASERI; n=3475), and the Finnish Type 1 Diabetes Prediction and Prevention Study (DIPP) Study subjects (n=7410). These children were observed for signs of beta-cell autoimmunity and progression to T1D, and the results obtained were compared between the FDRs and the general population cohorts. --- Results and conclusions. By combining HLA and autoantibody screening, T1D risks similar to those reported for autoantibody-positive FDRs are observed in the pediatric general population. Progression rate to T1D is high in genetically susceptible children with persistent multipositivity. Measurement of IAA affinity failed in stratifying the risk assessment in young IAA-positive children with HLA-conferred disease susceptibility, among whom affinity of IAA did not increase during the prediabetic period. Young age at seroconversion, increased weight-for-height, decreased early insulin response, and increased IAA and IA-2A levels predict T1D in young children with genetic disease susceptibility and signs of advanced beta-cell autoimmunity. Since the incidence of T1D continues to increase, efforts aimed at preventing T1D are important, and reliable disease prediction is needed both for intervention trials and for effective and safe preventive therapies in the future. Our observations confirmed that combined HLA-based screening and regular autoantibody measurements reveal similar disease risks in pediatric general population as those seen in prediabetic FDRs, and that risk assessment can be stratified further by studying glucose metabolism of prediabetic subjects. As these screening efforts are feasible in practice, the knowledge now obtained can be exploited while designing intervention trials aimed at secondary prevention of T1D.

Developmental, functional brain imaging and electrophysiological evidence of visual and auditory working memory

Intact function of working memory (WM) is essential for children and adults to cope with every day life. Children with deficits in WM mechanisms have learning difficulties that are often accompanied by behavioral problems. The neural processes subserving WM, and brain structures underlying this system, continue to develop during childhood till adolescence and young adulthood. With functional magnetic resonance imaging (fMRI) it is possible to investigate the organization and development of WM. The present thesis aimed to investigate, using behavioral and neuroimaging methods, whether mnemonic processing of spatial and nonspatial visual information is segregated in the developing and mature human brain. A further aim in this research was to investigate the organization and development of audiospatial and visuospatial information processing in WM. The behavioral results showed that spatial and nonspatial visual WM processing is segregated in the adult brain. The fMRI result in children suggested that memory load related processing of spatial and nonspatial visual information engages common cortical networks, whereas selective attention to either type of stimuli recruits partially segregated areas in the frontal, parietal and occipital cortices. Deactivation mechanisms that are important in the performance of WM tasks in adults are already operational in healthy school-aged children. Electrophysiological evidence suggested segregated mnemonic processing of visual and auditory location information. The results of the development of audiospatial and visuospatial WM demonstrate that WM performance improves with age, suggesting functional maturation of underlying cognitive processes and brain areas. The development of the performance of spatial WM tasks follows a different time course in boys and girls indicating a larger degree of immaturity in the male than female WM systems. Furthermore, the differences in mastering auditory and visual WM tasks may indicate that visual WM reaches functional maturity earlier than the corresponding auditory system. Spatial WM deficits may underlie some learning difficulties and behavioral problems related to impulsivity, difficulties in concentration, and hyperactivity. Alternatively, anxiety or depressive symptoms may affect WM function and the ability to concentrate, being thus the primary cause of poor academic achievement in children.

Microarrays in Molecular Profiling of Ewing Sarcoma Family of Tumors and CDKN2A Aberrations

Background: The Ewing sarcoma family of tumors (ESFT) are rare but highly malignant neoplasms that occur mainly in bone or but also in soft tissue. ESFT affects patients typically in their second decade of life, whereby children and adolescents bear the heaviest incidence burden. Despite recent advances in the clinical management of ESFT patients, their prognosis and survival are still disappointingly poor, especially in cases with metastasis. No targeted therapy for ESFT patients is currently available. Moreover, based merely on current clinical and biological characteristics, accurate classification of ESFT patients often fails at the time of diagnosis. Therefore, there is a constant need for novel molecular biomarkers to be applied in tandem with conventional parameters to further intensify ESFT risk-stratification and treatment selection, and ultimately to develop novel targeted therapies. In this context, a greater understanding of the genetics and immune characteristics of ESFT is needed. Aims: This study sought to open novel insights into gene copy number changes and gene expression in ESFT and, further, to enlighten the role of inflammation in ESFT. For this purpose, microarrays were used to provide gene-level information on a genomewide scale. In addition, this study focused on screening of 9p21.3 deletion sizes and frequencies in ESFT and, in another pediatric cancer, acute lymphocytic leukemia (ALL), in order to define more exact criteria for highrisk patient selection and to provide data for developing a more reliable diagnostic method to detect CDKN2A deletions. Results: In study I, 20 novel ESFT-associated suppressor genes and oncogenes were pinpointed using combined array CGH and expression analysis. In addition, interesting chromosomal rearrangements were identified: (1) Duplication of derivative chromosome der(22)(11;22) was detected in three ESFT patients. This duplication included the EWSR1-FLI1 fusion gene leading to increase in its copy number; (2) Cryptic amplifications on chromosomes 20 and 22 were detected, suggesting a novel translocation between chromosomes 20 and 22, which most probably produces a fusion between EWSR1 and NFATC2. In study II, bioinformatic analysis of ESFT expression profiles showed that inflammatory gene activation is detectable in ESFT patient samples and that the activation is characterized by macrophage gene expression. Most interestingly, ESFT patient samples were shown to express certain inflammatory genes that were prognostically significant. High local expression of C5 and JAK1 at the tumor site was shown to associate with favorable clinical outcome, whereas high local expression of IL8 was shown to be detrimental. Studies III and IV showed that the smallest overlapping region of deletion in 9p21.3 includes CDKN2A in all cases and that the length of this region is 12.2 kb in both Ewing sarcoma and ALL. Furthermore, our results showed that the most widely used commercial CDKN2A FISH probe creates false negative results in the narrowest microdeletion cases (<190 kb). Therefore, more accurate methods should be developed for the detection of deletions in the CDKN2A locus. Conclusions: This study provides novel insights into the genetic changes involved in the biology of ESFT, in the interaction between ESFT cells and immune system, and in the inactivation of CDKN2A. Novel ESFT biomarker genes identified in this study serve as a useful resource for future studies and in developing novel therapeutic strategies to improve the survival of patients with ESFT.

Visuaalis-spatiaalisten työmuistivalmiuksien yhteys (esi)matemaattisiin taitoihin ja merkitys osana matemaattisilta taidoiltaan heikkojen lasten ja nuorten kognitiivista profiilia

Tämän itsenäisistä osatutkimuksista koostuvan tutkimussarjan tavoitteena oli pyrkiä täydentämään kuvaa matemaattisilta taidoiltaan heikkojen lasten ja nuorten tiedonkäsittelyvalmiuksista selvittämällä, ovatko visuaalis-spatiaaliset työmuistivalmiudet yhteydessä matemaattiseen suoriutumiseen. Teoreettinen viitekehys rakentui Baddeleyn (1986, 1997) kolmikomponenttimallin ympärille. Työmuistikäsitys oli kuitenkin esikuvaansa laajempi sisällyttäen visuaalis-spatiaaliseen työmuistiin Cornoldin ja Vecchin (2003) termein sekä passiiviset varastotoiminnot että aktiiviset prosessointitoiminnot. Yhteyksiä työmuistin ja matemaattisten taitojen välillä tarkasteltiin viiden eri osatutkimuksen avulla. Kaksi ensimmäistä keskittyivät alle kouluikäisten lukukäsitteen hallinnan ja visuaalis-spatiaalisten työmuistivalmiuksen tutkimiseen ja kolme jälkimmäistä peruskoulun yhdeksäsluokkalaisten matemaattisten taitojen ja visuaalis-spatiaalisten työmuistitaitojen välisten yhteyksien selvittämiseen. Tutkimussarjan avulla pyrittiin selvittämään, ovatko visuaalis-spatiaaliset työmuistivalmiudet yhteydessä matemaattiseen suoriutumiseen sekä esi- että yläkouluiässä (osatutkimukset I, II, III, IV, V), onko yhteys spesifi rajoittuen tiettyjen visuaalis-spatiaalisten valmiuksien ja matemaattisen suoriutumisen välille vai onko se yleinen koskien matemaattisia taitoja ja koko visuaalis-spatiaalista työmuistia (osatutkimukset I, II, III, IV, V) tai työmuistia laajemmin (osatutkimukset II, III) sekä onko yhteys työmuistispesifi vai selitettävissä älykkyyden kaltaisella yleisellä päättelykapasiteetilla (osatutkimukset I, II, IV). Tutkimussarjan tulokset osoittavat, että kyky säilyttää ja käsitellä hetkellisesti visuaalis-spatiaalista informaatiota on yhteydessä matemaattiseen suoriutumiseen eikä yhteyttä voida selittää yksinomaan joustavalla älykkyydellä. Suoriutuminen visuaalis-spatiaalista työmuistia mittaavissa tehtävissä on yhteydessä sekä alle kouluikäisten esimatemaattisten taitojen hallintaan että peruskoulun yhdeksäsluokkalaisten matematiikan taitoihin. Matemaattisilta taidoiltaan heikkojen lasten ja nuorten visuaalis-spatiaalisten työmuistiresurssien heikkoudet vaikuttavat kuitenkin olevan sangen spesifejä rajoittuen tietyntyyppisissä muistitehtävissä vaadittaviin valmiuksiin; kaikissa visuaalis-spatiaalisen työmuistin valmiuksia mittaavissa tehtävissä suoriutuminen ei ole yhteydessä matemaattisiin taitoihin. Työmuistivalmiuksissa ilmenevät erot sekä alle kouluikäisten että kouluikäisten matemaattisilta taidoiltaan heikkojen ja normaalisuoriutujien välillä näyttävät olevan kuitenkin jossain määrin yhteydessä kielellisiin taitoihin viitaten vaikeuksien tietynlaiseen kasautumiseen; niillä matemaattisesti heikoilla, joilla on myös kielellisiä vaikeuksia, on keskimäärin laajemmat työmuistiheikkoudet. Osalla matematiikassa heikosti suoriutuvista on näin ollen selvästi keskimääräistä heikommat visuaalis-spatiaaliset työmuistivalmiudet, ja tämä heikkous saattaa olla yksi mahdollinen syy tai vaikeuksia lisäävä tekijä heikon matemaattisen suoriutumisen taustalla. Visuaalis-spatiaalisen työmuistin heikkous merkitsee konkreettisesti vähemmän mentaalista prosessointitilaa, joka rajoittaa oppimista ja suoritustilanteita. Tiedonkäsittelyvalmiuksien heikkous liittyy nimenomaan oppimisnopeuteen, ei asioiden opittavuuteen sinänsä. Mikäli oppimisympäristö ottaa huomioon valmiuksien rajallisuuden, työmuistiheikkoudet eivät todennäköisesti estä asioiden oppimista sinänsä. Avainsanat: Työmuisti, visuaalis-spatiaalinen työmuisti, matemaattiset taidot, lukukäsite, matematiikan oppimisvaikeudet

The Nature, Origins, and Consequences of Finnish Shame-Proneness: A Grounded Theory Study

Although shame is a universal human emotion and is one of the most difficult emotions to overcome, its origins and nature as well as its effects on psychosocial functioning are not well understood or defined. While psychological and spiritual counselors are aware of the effects and consequences of shame for an individual s internal well-being and social life, shame is often still considered a taboo topic and is not given adequate attention. This study aims to explain the developmental process and effects of shame and shame-proneness for individuals and provide tools for practitioners to work more effectively with their clients who struggle with shame. This study presents the empirical foundation for a grounded theory that describes and explains the nature, origins, and consequences of shame-proneness. The study focused on Finnish participants childhood, adolescence and adulthood experiences and why they developed shame-proneness, what it meant for them as children and adolescents and what it meant for them as adults. The data collection phase of this study began in 2000. The participants were recruited through advertisements in local and country-wide newspapers and magazines. Altogether 325 people responded to the advertisements by sending an essay concerning their shame and guilt experiences. For the present study, 135 essays were selected and from those who sent an essay 19 were selected for in-depth interviews. In addition to essays and interviews, participants personal notebooks and childhood hospital and medical reports as well as their scores on the Internalized Shame Scale were analyzed. The development of shame-proneness and significant experiences and events during childhood and adolescence (e.g., health, parenting and parents behavior, humiliation, bullying, neglect, maltreatment and abuse) are discussed and the connections of shame-proneness to psychological concepts such as self-esteem, attachment, perfectionism, narcissism, submissiveness, pleasing others, heightened interpersonal subjectivity, and codependence are explained. Relationships and effects of shame-proneness on guilt, spirituality, temperament, coping strategies, defenses, personality formation and psychological health are also explicated. In addition, shame expressions and the development of shame triggers as well as internalized and externalized shame are clarified. These connections and developments are represented by the core category lack of gaining love, validation and protection as the authentic self. The conclusions drawn from the study include a categorization of shame-prone Finnish people according to their childhood and adolescent experiences and the characteristics of their shame-proneness and personality. Implications for psychological and spiritual counseling are also discussed. Key words: shame, internalized shame, external shame, shame development, shame triggers, guilt, self-esteem, attachment, narcissism, perfectionism, submissiveness, codependence, childhood neglect, childhood abuse, childhood maltreatment, emotional abuse, sexual abuse, spiritual abuse, psychological well-being

Neuromagnetic studies on cortical somatosensory functions in infants and children : Normal development and effect of early brain lesions

Until recently, objective investigation of the functional development of the human brain in vivo was challenged by the lack of noninvasive research methods. Consequently, fairly little is known about cortical processing of sensory information even in healthy infants and children. Furthermore, mechanisms by which early brain insults affect brain development and function are poorly understood. In this thesis, we used magnetoencephalography (MEG) to investigate development of cortical somatosensory functions in healthy infants, very premature infants at risk for neurological disorders, and adolescents with hemiplegic cerebral palsy (CP). In newborns, stimulation of the hand activated both the contralateral primary (SIc) and secondary somatosensory cortices (SIIc). The activation patterns differed from those of adults, however. Some of the earliest SIc responses, constantly present in adults, were completely lacking in newborns and the effect of sleep stage on SIIc responses differed. These discrepancies between newborns and adults reflect the still developmental stage of the newborns’ somatosensory system. Its further maturation was demonstrated by a systematic transformation of the SIc response pattern with age. The main early adult­like components were present by age two. In very preterm infants, at term age, the SIc and SIIc were activated at similar latencies as in healthy fullterm newborns, but the SIc activity was weaker in the preterm group. The SIIc response was absent in four out of the six infants with brain lesions of the underlying hemisphere. Determining the prognostic value of this finding remains a subject for future studies, however. In the CP adolescents with pure subcortical lesions, contrasting their unilateral symptoms, the SIc responses of both hemispheres differed from those of controls: For example the distance between SIc representation areas for digits II and V was shorter bilaterally. In four of the five CP patients with cortico­subcortical brain lesions, no normal early SIc responses were evoked by stimulation of the palsied hand. The varying differences in neuronal functions, underlying the common clinical symptoms, call for investigation of more precisely designed rehabilitation strategies resting on knowledge about individual functional alterations in the sensorimotor networks.

Pharmacokinetics, efficacy, and safety of pravastatin in children : Studies in children with heterozygous familial hypercholesterolemia and in pediatric cardiac transplant recipients

Background. Hyperlipidemia is a common concern in patients with heterozygous familial hypercholesterolemia (HeFH) and in cardiac transplant recipients. In both groups, an elevated serum LDL cholesterol level accelerates the development of atherosclerotic vascular disease and increases the rates of cardiovascular morbidity and mortality. The purpose of this study is to assess the pharmacokinetics, efficacy, and safety of cholesterol-lowering pravastatin in children with HeFH and in pediatric cardiac transplant recipients receiving immunosuppressive medication. Patients and Methods. The pharmacokinetics of pravastatin was studied in 20 HeFH children and in 19 pediatric cardiac transplant recipients receiving triple immunosuppression. The patients ingested a single 10-mg dose of pravastatin, and plasma pravastatin concentrations were measured up to 10/24 hours. The efficacy and safety of pravastatin (maximum dose 10 to 60 mg/day and 10 mg/day) up to one to two years were studied in 30 patients with HeFH and in 19 cardiac transplant recipients, respectively. In a subgroup of 16 HeFH children, serum non-cholesterol sterol ratios (102 x mmol/mol of cholesterol), surrogate estimates of cholesterol absorption (cholestanol, campesterol, sitosterol), and synthesis (desmosterol and lathosterol) were studied at study baseline (on plant stanol esters) and during combination with pravastatin and plant stanol esters. In the transplant recipients, the lipoprotein levels and their mass compositions were analyzed before and after one year of pravastatin use, and then compared to values measured from 21 healthy pediatric controls. The transplant recipients were grouped into patients with transplant coronary artery disease (TxCAD) and patients without TxCAD, based on annual angiography evaluations before pravastatin. Results. In the cardiac transplant recipients, the mean area under the plasma concentration-time curve of pravastatin [AUC(0-10)], 264.1 * 192.4 ng.h/mL, was nearly ten-fold higher than in the HeFH children (26.6 * 17.0 ng.h/mL). By 2, 4, 6, 12 and 24 months of treatment, the LDL cholesterol levels in the HeFH children had respectively decreased by 25%, 26%, 29%, 33%, and 32%. In the HeFH group, pravastatin treatment increased the markers of cholesterol absorption and decreased those of synthesis. High ratios of cholestanol to cholesterol were associated with the poor cholesterol-lowering efficacy of pravastatin. In cardiac transplant recipients, pravastatin 10 mg/day lowered the LDL cholesterol by approximately 19%. Compared with the patients without TxCAD, patients with TxCAD had significantly lower HDL cholesterol concentrations and higher apoB-100/apoA-I ratios at baseline (1.0 ± 0.3 mmol/L vs. 1.4 ± 0.3 mmol/L, P = 0.031; and 0.7 ± 0.2 vs. 0.5 ± 0.1, P = 0.034) and after one year of pravastatin use (1.0 ± 0.3 mmol/L vs. 1.4 ± 0.3 mmol/L, P = 0.013; and 0.6 ± 0.2 vs. 0.4 ± 0.1, P = 0.005). Compared with healthy controls, the transplant recipients exhibited elevated serum triglycerides at baseline (median 1.3 [range 0.6-3.2] mmol/L vs. 0.7 [0.3-2.4] mmol/L, P=0.0002), which negatively correlated with their HDL cholesterol concentration (r = -0.523, P = 0.022). Recipients also exhibited higher apoB-100/apoA1 ratios (0.6 ± 0.2 vs. 0.4 ± 0.1, P = 0.005). In addition, elevated triglyceride levels were still observed after one year of pravastatin use (1.3 [0.5-3.5] mmol/L vs. 0.7 [0.3-2.4] mmol/L, P = 0.0004). Clinically significant elevations in alanine aminotransferase, creatine kinase, or creatinine ocurred in neither group. Conclusions. Immunosuppressive medication considerably increased the plasma pravastatin concentrations. In both patient groups, pravastatin treatment was moderately effective, safe, and well tolerated. In the HeFH group, high baseline cholesterol absorption seemed to predispose patients to insufficient cholesterol-lowering efficacy of pravastatin. In the cardiac transplant recipients, low HDL cholesterol and a high apoB-100/apoA-I ratio were associated with development of TxCAD. Even though pravastatin in the transplant recipients effectively lowered serum total and LDL cholesterol concentrations, it failed to normalize their elevated triglyceride levels and, in some patients, to prevent the progression of TxCAD.

Immunological Effects of Probiotic Bacteria in Prevention and Treatment of Allergic Diseases in Children

Epidemiological and experimental studies suggest that changes in gut microbial balance are associated with increases in the prevalence of allergic diseases. Probiotics are proposed to provide beneficial immunoregulatory signals which aid in oral tolerance achievement and alleviation of symptoms of allergic diseases. The present study evaluates both the immunological mechanisms of probiotics in infants with allergic diseases and their preventive aspect among infants prone to allergy. Furthermore, the purpose of the study was to characterise the immunological features of cord blood mononuclear cells (CBMCs) in infants at high genetic risk for allergy. GATA-3 expression (p = 0.03), interleukin (IL) -2(p = 0.026), and IL-5 (p = 0.013) secretion of stimulated CBMCs were higher in IgE-sensitized infants at age 2 than in non-allergic, non-sensitized infants. Lactobacillus GG (LGG) treatment increased secretion of IFN-γ by PBMCs in vitro in infants with cow s milk allergy (CMA) (p = 0.006) and in infants with IgE-associated eczema (p = 0.017), when compared to levels in the placebo group. A probiotic mixture, increased secretion of IL-4 by PBMCs in vitro in infants with CMA (p = 0.028), when compared with placebo-group levels. The LGG treatment induced higher plasma C-reactive protein (CRP) (p = 0.021) and IL-6 (p = 0.036) levels in infants with IgE-associated eczema than in the placebo group. The probiotic mixture induced higher plasma IL-10 levels in infants with eczema (p = 0.016). In the prevention study of allergic dis-eases, the infants receiving the probiotic mixture had higher plasma levels of CRP (p = 0.008), total IgA (p = 0.016), total IgE (p = 0.047), and IL-10 (p = 0.002) than did infants in the placebo group. Increased CRP level at age 6 months was associated with a decreased risk for eczema at age 2 not only in the infants who received probiotics but also in the placebo group (p = 0.034). In conclusion, the priming of the GATA-3 and IL-5 pathway can occur in utero, and a primary feature of T-cells predisposing to IgE-sensitization seems to directly favour Th2 deviation. LGG treatment induced increased plasma levels of CRP and IL-6 in infants with IgE-associated eczema, suggesting an activation of innate immu-nity. The probiotic mixture, when given to allergy-prone infants, induced inflammation, detected as increased plasma CRP levels, which at age 6 months was associated with decreased risk for eczema at age 2.The probiotic-induced response in allergy prone infants was characterized by their higher plasma IL-10, total IgE, and CRP levels, without induction of an allergen-specific IgE response. In this respect, the probiotics in infancy appear to induce protective immune profiles that are characteristic for chronic low-grade inflammation, a response resembling that of helminth-like infections.