Type 1 diabetes (T1D) is a chronic disease caused by destruction of the insulin producing beta-cells in the pancreas. The incidence of T1D has increased rapidly, especially in the Western world and among young children. The pathogenesis of T1D is not fully understood, but the beta-cells are believed to be destroyed by an autoimmune process initiated years before the onset of T1D. During this pre-clinical period, autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and the tyrosine phosphatase-like protein IA-2 (IA-2A) can be detected and are used to identify individuals at risk of T1D. The major genetic determinant for T1D is the HLA class II genes, but also polymorphism in the insulin gene and CTLA-4 gene are associated with T1D. The risk genes cannot explain the rapid increase in incidence of T1D, therefore a role for different environmental factors has been suggested. The aim was to study the prevalence of beta-cell autoantibodies in children from the general population in relation to known genetic and environmental risk factors, and in young patients with T1D in high and low incidence areas. Short duration of breast-feeding was associated with an increased risk of developing beta-cell autoantibodies in children from the general population at 5-6 years of age. We found an association between positivity for GADA and/or IAA at the age of 5-6 years and a short duration of total breastfeeding, and also between positivity for GADA, IA-2A and/or IAA and a short duration of exclusive breast-feeding. Our findings suggest that breast-feeding has a long term protective effect on the risk of beta-cell autoimmunity in children from the general population. The T1D related risk genes were not associated with beta-cell autoantibodies other than GADA in children from the general population at 5-6 years of age. Children with the DR4-DQ8 haplotype were more often positive for GADA than children without this haplotype. We found no association of GADA with DR3-DQ2 haplotype or between these two haplotypes and any of the other autoantibodies. Our results suggest that beta-cell autoimmunity in children from the general population is not strongly associated with any risk genes of T1D other than DR4-DQ8. In the non-diabetic children with allergic heredity GADA was detectable in almost all children, IA-2A in about half and IAA in 10% of the children. The levels low of these autoantibodies fluctuated with age and different patterns of fluctuations were seen for GADA and IA-2A, which may reflect differences in the immune response to the autoantigens. In patients with newly diagnosed T1D, we found some differences between patients from a high incidence country (Sweden) and a country with a lower incidence (Lithuania). Among the Swedish patients, the prevalence of IAA and GADA or multiple autoantibodies was higher than in Lithuanian patients. The risk genes DR4-DQ8 and the heterozygous high risk combination DR4-DQ8/DR3-DQ2 was more common among the Swedish patients than Lithuanian patients. Patients with low levels of IAA had higher levels of HbA1c and ketones, indicating that patients without IAA or with low levels of IAA have a more severe onset of T1D. Our findings indicate that beta-cell autoimmunity is more pronounced in a high incidence area compared to an area with a lower incidence. In conclusion, short duration of breast-feeding is a risk factor for beta-cell autoantibodies in children from the general population, and the beta-cell autoantibodies in these children are not associated with specific risk genes. Children with newly diagnosed T1D in a high incidence area carry risk genes and have autoantibodies more often than newly diagnosed children from an area with a lower incidence, perhaps indicating different disease phenotypes.

Globally, neonatal mortality has remained basically unchanged for the last three to four decades and every year almost four million newborns die before reaching one month of age. This persistent mortality is related to an invisibility of the newborn child in policies and statistics and a neglect of health care decision-makers, planners and practitioners to deliver a perinatal continuum of care. In recent years attention has however been brought to the unchanged neonatal mortality in an effort to improve survival. The present thesis seeks to increase understanding of obstacles for better neonatal survival. The studies performed are undertaken as sub-studies to the NeoKIP project in Quang Ninh province in northern Vietnam, a randomized controlled trial of knowledge implementation for improved neonatal survival (Neonatal Health – Knowledge Into Practice, ISRCTN 44599712). In the first paper we investigated and discussed the scope of invisibility of neonatal mortality through measuring the accuracy of official statistics on neonatal deaths. The second paper reports an inquiry of determinants of neonatal mortality by use of a population-based case-referent design. Paper III and IV analyse delivery care utilization and care seeking patterns prior to and at delivery using narratives and GIS technique. There was a substantial under-reporting of neonatal mortality in the official statistics, with study results showing a four times higher neonatal mortality rate in Quang Ninh province than reported to the Ministry of Health. This neonatal mortality rate of 16/1000 live births (as compared to 4.2/1000 in official reports) was unevenly distributed in the province, showing large geographical discrepancies. In the rural and remote areas of Vietnam education level is lower and the concentrations of ethnic minorities and poor households are higher. Ethnic minority belonging was associated with a more than doubled risk of neonatal death compared to the hegemonic group of Kinh (OR 2.08 CI 95 % 1.39 – 3.10). This increased risk was independent of household economic status or maternal education level. Neonatal mortality was also associated with home deliveries, non-attendance to antenatal care and distance to the health care facilities. However, ethnic minority mothers still had an increased risk of experiencing a neonatal death even if they attended antenatal care, delivered at or lived close to a health facility. The invisibility of the neonatal period in health information systems hides the true width of the neonatal mortality challenge. By not acknowledging the problem, the marginalization of already disadvantaged groups continues, leaving ethnic minority babies with an elevated risk of dying during the first month in life. This example of ethnic inequity highlights the importance to target those most in need. The studies of the present thesis should therefore be looked upon as a contribution to the struggle to illuminate the global burden of neonatal mortality.

Despite major advances in our understanding of the biology of childhood acute myeloid leukemia (AML) and the development of new cytotoxic drugs, the prognosis of long-term survival is still only 60-65 %. In the present research, we studied the pharmacokinetics of drugs used in the induction therapy of childhood AML and performed in vitro drug sensitivity testing of leukemic cells from children with AML. The aims of the studies were to correlate the results of the analysis to biological and clinical parameters and to identify subgroups of AML with specific drug sensitivity profiles in order to better understand why treatment fails in some patients and how therapy may be improved. Blood samples were analysed to study the pharmacokinetics of doxorubicin (n=41), etoposide (n=45) and 6-thioguanine (n=50). Doxorubicin plasma concentration and total body clearance were correlated to the effect of induction therapy, and doxorubicin plasma concentration was an independent factor for complete remission, both in univariate and multivariate analysis including sex, age, and white blood cell count at diagnosis. For etoposide and 6-thioguanine no correlation was found between pharmacokinetics and clinical effect. Children with Down syndrome (DS) tended to reach higher blood concentrations of etoposide and thioguanine nucleotides, indicating that dose reduction may be reasonable to reach the same drug exposure as in children without DS. Leukemic cells from 201 children with newly diagnosed AML, 15 of whom had DS, were successfully analysed for in vitro drug sensitivity by the fluorometric microculture cytotoxicity assay (FMCA). We found that samples from children with DS were highly sensitive to most drugs used in AML treatment. In non-DS children, the t(9;11) samples were significantly more sensitive to cytarabine (p=0.03) and doxorubicin (p=0.035) than other samples. The findings might explain the very favorable outcome reported in children with DS and t(9;11)-positive AML. A specific drug resistance profile was found for several other genetic subgroups as well. A detailed study of MLL-rearranged leukemia showed that cellular drug sensitivity is correlated both to partner genes and cell lineage, findings that support the strategy of contemporary protocols to include high-dose cytarabine in the treatment of patients with MLL-rearrangement, both in AML and acute lymphoblastic leukemia (ALL). Our results indicate that drug resistance and pharmacokinetic studies may yield important information regarding drug response in different sub-groups of childhood AML, helping us to optimize future chemotherapy in childhood AML.

To coordinate visual perception and motor control in daily life where we are constantly surrounded by motion, we are dependent on normal visuomotor capacity. One essential prerequisite for normal visuomotor capacity is smooth pursuit eye movements (SP). Infants born very preterm (VPT = born <32 gestational weeks) are at high risk of developing disabilities in higher brain functions i.e. perception, cognition, concentration and coordination. In this thesis visuomotor capacity was investigated in a cohort of VPT infants (n = 113) and compared to control groups of full term (FT) infants. Levels of SP were measured at 2 and 4 months’ corrected age (CA). At 8 months’ CA reaching capacity toward a moving object was evaluated as this represents an executive activity guided by vision that develops at an early age. Lower levels of SP were found in the VPT infants compared to FT controls. The VPT boys showed higher levels of SP compared to the VPT girls. In VPT infants without major neonatal morbidities lower levels of SP was found compared to the FT controls. No difference in total capacity of gaze tracking was found, although the VPT infants lagged the object more at 4 months’ CA and used more saccades at 2 months’ CA. With age the VPT infants’ SP levels increased, but with a wider dispersion compared to the FT controls, and the levels of SP at 4 months’ CA corresponded to the levels of the FT infants at 2 months.  A number of perinatal risk factors were found to be negatively associated to lower levels of SP, and this effect was more pronounced in VPT infants with multiple risk factors,.  When evaluating the capacity to reach a moving object at 8 months’ CA, the VPT infants showed significantly more bimanual reach and more curved reaching paths to catch the object as compared to the FT control group. In conclusion, a delayed visuomotor capacity was found in VPT infants compared to FT control infants at 2, 4 and 8 months’ CA. Some VPT infants with perinatal risk factors did not develop in levels of SP between 2 and 4 months’ CA.

<p>Variation of diabetes incidence over time in countries with different incidence levels and socio-economic conditions, and in an age span beyond the childhood years, may give clues for diabetes causes.</p><p><i>Materials:</i> Data from prospective type 1 diabetes registers in Sweden and Lithuania in children (0-14 years) and young adults (15-34 and 15-39 years, respectively). Number of infections recorded in health care booklets (117 cases; 270 controls); interview about the dietary intake one-year before the diagnosis and routinely recorded growth data (99 cases; 180 controls). </p><p><i>Results:</i> The incidence of type 1 diabetes in Sweden and Lithuania differed most in the younger age groups, 28.9 and 7.5/100,000/year in 0-14-year group, respectively. During 1983-2000 incidence increased in 0-14-year old children in both countries, but the pattern of change differed. During 1983-1998 the incidence increased in Swedish children, but tended to decrease in young adults, with no increase in the age group below 35 years, indicating that the increase of childhood diabetes may be due to a shift towards a younger age at diagnosis. Within a low-incidence country Lithuania there was an urban-rural gradient of incidence, especially in the younger age groups, that seemed to follow poverty distribution: incidence in the 0-39-year group was 7.1, 9.0 and 8.8/100,000/year in rural areas, towns and cities, respectively, p<0.001.</p><p>Exposure to one or more non-specific infection during the first half-year of life reduced diabetes risk: odds ratios (95%-CI) in 0-14 and 5-14-year groups were (0.60; 0.37-0.98) and (0.47; 0.26-0.87), respectively. Higher energy intake and weight-for-age were independent diabetes risk factors: odds ratios for medium and high levels of energy were 1.33 (0.52-3.42) and 5.23 (1.67-16.38), and for weight-for-age 3.20 (1.30-7.88) and 3.09 (1.16-8.22), respectively. High intake of carbohydrates, disaccharides and sucrose in particular, increased diabetes risk independently of the high intake of energy.</p><p><i>Conclusion:</i> Environmental factors associated with socio-economic conditions in childhood may be important for the occurrence of type 1 diabetes. Lack of exposure to microbial antigens early in life, higher intake of energy and more rapid growth may contribute to the increase of childhood-onset diabetes observed in many countries.</p>

<p><strong>Aim:</strong> The aim of this study was to describe the total energy expenditure (TEE) and physical activity levels (PAL) within a group of children with cystic fibrosis (CF) and to compare the results with a control group with healthy children. The aim also was to compare the rated activity levels between the groups as well comparing the difference between boys and girls within the groups. <strong>Method:</strong> The study included 30 participating children, divided into two groups with 15 participants in each group. One of the groups was a CF-group and the other a group of controls, matched for gender and age. Activity diaries were studied and data were presented decrepitly and analyzed with Wilcoxon rank sum test. <strong>Result:</strong> The result showed no difference between the groups while comparing TEE and PAL. Half of the participants in both groups (53,34 % and 46,67 %) reached a moderate or high physical activity level during the registration. No significance was proved between the groups as they rated their activity level, numbered 6-9, in their activity diaries. Neither could any differences be proved significant in rated activity between the boys and girls within the groups. <strong>Conclusion:</strong> The conclusion was that no significant differences appeared regarding TEE or PAL between the CF-group and the control group participating in this study. Neither were there any differences in activity level between boys and girls within the groups.</p> / <p><strong>Syfte:</strong> Syftet med studien var att beskriva energiomsättning och fysisk aktivitetsnivå hos en grupp barn med cystisk fibros (CF) och jämföra resultatet med friska barn i en kontrollgrupp. Syftet var också att jämföra skattade aktivitetsnivåer mellan grupperna samt mellan flickor och pojkar inom de båda grupperna. <strong>Metod:</strong> I studien deltog 30 barn, indelade i två grupper om 15 deltagare. Grupperna var en CF-grupp och en kontrollgrupp matchad efter kön och ålder. Aktivitetsdagböcker granskades och data sammanställdes och data presenterades deskriptivt och analyserades med Wilcoxsons rangsummetest. <strong>Resultat:</strong> Resultatet visade att det inte fanns skillnad mellan de båda grupperna vid jämförelse av TEE och PAL. Ungefär hälften av alla deltagare (53,34 % resp. 46,67 %) nådde moderat eller hög aktivitetsnivå under de registrerade dagarna. Det förekom ingen signifikant skillnad mellan grupperna med avseende antal skattade 6-9:or i aktivitetsdagboken. Inte heller någon skillnad mellan könen inom de båda grupperna kunde påvisas. <strong>Slutsats:</strong> Slutsatsen var att det inte fanns någon signifikant skillnad beträffande energiomsättning eller fysisk aktivitet mellan barn med CF och friska barn som deltog i denna studie. Inte heller kunde någon skillnad i aktivitetsnivå mellan könen inom grupperna påvisas.</p>

<p>To assess the impact of congenital malformations in Down syndrome (DS) on morbidity, mortality and outcome at birth, information on all children with DS born in the northern part of Sweden in 1973-80 (n=211) and 1995-98 (n=88) was collected. Most common were congenital heart defects (CHD), dominated by atrioventricular septal defects (AVSD). Up to age 10 years, morbidity and mortality were more than 10 times higher in DS children with CHD than in healthy DS children. The DS children seemed more vulnerable at birth than Swedish children in general: they had increased frequencies of Cesarean sections, premature birth, asphyxia, and low birthweight, and higher proportions of children small for gestational age, regardless of the presence of CHD. Infant mortality decreased from 14.2% to 2.3% between the two periods.</p><p>All children with AVSD with and without DS born in Sweden 1973-1997 (n=801) were followed up retrospectively to 2001. Children with isolated AVSD without complex additional CHDs were studied more closely (n=502). A reduction in age at operation and postoperative mortality (from 28 to 1%) was observed. No significant difference in 5-year postoperative mortality between genders or between DS and non-DS children was found. The 5-year postoperative mortality in DS decreased from 35% in 1973-77 to about 10% in 1993-97. </p><p>CHD had a major influence on morbidity, infectionrate and mortality in DS, but not on DS birth variables. The formerly high mortality in CHD is now reduced. In isolated AVSD measures seem equally successful in DS and non-DS children. Mortality is still 3 times higher in DS children with isolated AVSD than in healthy DS children. </p>

<p>The overall aim of this thesis was to study the implementation of guidelines, change processes and contextual variables from the perspective of improvements and neonatal nursing care’s endeavours to be more evidenced-based. Because health care is exposed to extensive change pressure and because the impact of effectiveness research on clinical practice is limited, it becomes urgent to understand how knowledge utilisation initiatives can be facilitated.</p><p>Three studies involved managers and nurses at all neonatal units in Sweden. Two of these studies also included nurses from other healthcare organisations. The fourth study included all staff at four neonatal units. The study designs used were cross-sectional, comparative and prospective longitudinal surveys; questionnaires were used as data collection tools in all four studies.</p><p>Evaluation of the utilisation of the neonatal nursing guidelines showed that the guidelines were known to the nurse managers and used at most of the units, though to varying degrees and in different ways. Fifteen months after guideline dissemination, 8 of 35 units had changed practice, of which 2 units had completed the implementation process of a guideline. Involvement in the preceding guideline project facilitated the completion of improvement projects compared with participation in training courses for quality improvement (QI) only. There was no difference between these two groups on long-standing involvement in improvement work. Nurses who continued QI work over a 4-year period were more active in seeking research and implementing research findings in clinical practice than those who ceased the improvement work. The QI-sustainable nurses reported better contextual support for research-related activities. In a separate study staff perceptions of organisational factors appeared stable over the course of one year at the aggregated level. Improvements in skills development and participatory management predicted higher overall organisational and staff well-being. </p><p>The findings emphasize the importance of including both individual and organisational factors in the strategic planning for evidence-based nursing. Plans have to be long-term and consider that change is a slow process. Leadership commitment is essential and there are clear benefits in developing a learning and professional supportive environment as well as of involving staff in organisational decision making.</p>

<p>Fifty children with hematologic malignancies have been treated with autologous BMT in Uppsala. The aim was to describe late effects in this group with special reference to cataracts, reduced final height, and to hepatic, renal, and pulmonary late effects. </p><p>Cataracts: All patients who received TBI in their conditioning developed posterior subcapsular cataract after BMT. A few patients with visual impairment affecting daily life needed cataract surgery, whereas the visual acuity was well preserved in most of the other patients.</p><p>Final height: There was a decrease in final height relative both to height at BMT and to target height. This decrease was significant both in those who had received TBI only and in those who had been given cranial irradiation. Cranial irradiation, young age at BMT, and short duration of GH treatment were predictors of height loss. </p><p>Hepatic function: Hepatic function was well preserved over a period of 10 years after BMT. TBI did not appear to be a risk factor for hepatic impairment. </p><p>Renal function: Six months after BMT there was a decrease in renal function in patients who had received TBI. It then recovered, albeit incompletely, and stabilized. After the first year there was little change over a period of 10 years after BMT. TBI appeared to be the most important risk factor for the development of chronic renal impairment in a number of patients. Nephrotoxic antibiotics may have contributed.</p><p>Pulmonary function: Six months after BMT there was a decrease in pulmonary function in those who received TBI. It then recovered and stabilized at the pretransplant level. After the first year there was little change over a period of 10 years after BMT. TBI appeared to be the most important risk factor for restrictive pulmonary disease in a number of patients whereas chemotherapy might also have been of importance for impaired gas exchange.</p>

<p>Rolandic epilepsy (RE) is the most common focal epilepsy syndrome in the pediatric age group with an onset between 3 and 13 years. The syndrome is defined by electro-clinically typical features and has been considered benign according to seizure remission before the age of 16 years.</p><p>The aim of this thesis was to investigate children with typical RE with different methods and to discuss the delineation of the syndrome. Thirty-eight children, aged 6–14 years, participated in one up to four studies.</p><p>Eighteen children were investigated with MRI. Hippocampal abnormalities were found in six (33%), volume asymmetry in five (28%) and high signal intensities on T2-weighted images in three (17%). Additionally, high signal intensities in T2-weighted images were revealed subcortically in temporal and frontal lobes bilaterally in five children (28%).</p><p>The hippocampal region was evaluated metabolically using proton magnetic resonance spectroscopy (¹H-MRS) in 13 children with RE and 15 matched controls. A metabolic asymmetry of the hippocampal regions was found in the patients compared to controls indicating an abnormal neuronal function.</p><p>Seventeen children with RE and 17 matched controls were investigated with a neuropsychological test battery. The RE children showed lower performance in auditory-verbal tests and in executive functions compared to controls.</p><p>Twenty RE children and 24 controls were assessed concerning their oromotor function. The RE children had greater problems concerning tongue movements including articulation. A dichotic listening test was also performed in a subgroup showing poorer results in the RE group. </p><p>A simple classification is proposed with RE ‘pure’ as the main group and the frame for this study.</p><p>In conclusion, these investigations disclosed various abnormalities in children with RE, challenging the benign concept during the active phase. It is assumed that maturational factors comprise causal mechanism to the deviant findings, which probably successively will normalize.</p>