<p>Excessive weight gain has frequently been reported in adolescents with type 1 diabetes, especially in girls. In general, puberty is associated with reduced insulin sensitivity that is further diminished by overweight. The causes and consequences of excessive weight gain in adolescents with type 1 diabetes are not fully understood. The studies described in this thesis addressed body composition in adolescents with type 1 diabetes and the relationships between physical activity, energy intake and changes in body composition. Furthermore, the effect of metformin as additional therapy on glycaemic control and insulin sensitivity was examined in a randomised placebo-controlled study. Body mass index (BMI) and percentage body fat (%BF) were significantly higher in girls with type 1 diabetes compared to healthy control girls. Mean HbA1c during puberty, but not mean insulin dose, was positively related to BMI at the age of 18 in girls with diabetes. A centralised fat distribution was associated with poor glycaemic control, increased daily dosage of insulin and elevated cholesterol and triglyceride levels. Neither total physical activity nor total energy intake differed between adolescent girls with type 1 diabetes and healthy age-matched control girls. A high dietary fat intake was positively related to gain in %BF in girls with type 1 diabetes. Additional therapy with metformin for three months improved glycaemic control and peripheral insulin sensitivity in adolescents with poorly controlled type 1 diabetes. The improvement in glycaemic control was related to insulin sensitivity at baseline, implying that the most insulin resistant subjects benefited most from the metformin therapy. It is concluded that the excessive weight gain observed in girls with type 1 diabetes is mainly attributable to an increased fat mass and that dietary fat intake is of importance for this gain in body fat. Additional treatment with metformin improves glycaemic control in adolescents with poorly controlled type 1 diabetes.</p>

<p>The process of β-cell destruction that leads to type 1 diabetes (T1D) is incompletely understood and it is believed to be a result of both genetic and environmental factors. Enterovirus (EV) infections of the β-cells have been proposed to be involved, however, the effects of EV infections on human β-cells have been little investigated. This thesis summarises studies of three different Coxsackie B4 virus strains that have previously been shown to infect human islets. The effects of infections with these EV were studied <i>in vitro</i> in human islets and in a rat insulin-producing cell line. In addition, a pilot study was performed on isolated human islets to investigate the ability to treat such infections with an antiviral compound.</p><p>It was found that one of the virus strains replicated in human β-cells without affecting their main function for at least seven days, which <i>in vivo</i> may increase a virus’s ability to persist in islets.</p><p>Nitric oxide was induced by synthetic dsRNA, poly(IC), but not by viral dsRNA in rat insulinoma cells in the presence of IFN-γ, suggesting that this mediator is not induced by EV infection in β-cells and that poly(IC) does not mimic an EV infection in this respect.</p><p>All three virus strains were able to induce production of the T-cell chemoattractant interferon-γ-inducible protein 10 (IP-10) during infection of human islets, suggesting that an EV infection of the islets might trigger insulitis <i>in vivo</i>.</p><p>Antiviral treatment was feasible in human islets, but one strain was resistant to the antiviral compound used in this study.</p><p>To conclude, a potential mechanism is suggested for the involvement of EV infections in T1D. If EV infections induce IP-10 production in human islet cells <i>in vivo</i>, they might recruit immune cells to the islets. Together with viral persistence and/or virus-induced β-cell damage, this might trigger further immune-mediated β-cell destruction <i>in vivo</i>.</p>

Chlamydia pneumoniae is a human respiratory tract pathogen. Seroepidemiological studies indicate that C. pneumoniae infection is most common in school-aged children and infrequently detected in younger children. The aims of this study were to further elucidate the prevalence of C. pneumoniae in paediatric populations and to describe the clinical implications of these infections. The study population consisted of 367 children with respiratory tract diseases, 453 presumed healthy children at day-care, 69 children undergoing adenoidectomy and 1585 children from a population based cohort. Family members to infected day-care children were investigated. The laboratory methods used were polymerase chain reaction (PCR) on specimen from upper respiratory tract, serology by microimmunofluorescence (MIF), and immunohistochemistry (IHC) on adenoid tissue specimen. Personal data and medical history were obtained by the means of questionnaires and by the study of patient records. In children younger than five years, the prevalence of C. pneumoniae was 17% as detected by PCR. This prevalence started to increase with increasing age from two years of age. The corresponding increase in serology as detected by MIF started at the age of four years. The prevalence at day-care centres varied from 4 to 39%. Both PCR and MIF underestimated the prevalence of C. pneumoniae detected by IHC. Families to infected children were investigated: mothers were more often infected than fathers were. Most C. pneumoniae infections in small children were confined to the upper respiratory tract. These infections were usually mild or asymptomatic. Symptomatic disease may be of prolonged nature. No subsequent illness after C. pneumoniae infection was detected at follow-up after four years. In general, no association between C. pneumoniae and asthma was found, but C. pneumoniae may be of importance for asthma in some susceptible individuals. Previous C. pneumoniae infection reduced the risk for later atopy. In conclusion, C. pneumoniae is a common finding in small children and most often causes relatively mild disease. If the acquisition of this infection early in life will have any implications for future health remains to be investigated.

Excessive weight gain has frequently been reported in adolescents with type 1 diabetes, especially in girls. In general, puberty is associated with reduced insulin sensitivity that is further diminished by overweight. The causes and consequences of excessive weight gain in adolescents with type 1 diabetes are not fully understood. The studies described in this thesis addressed body composition in adolescents with type 1 diabetes and the relationships between physical activity, energy intake and changes in body composition. Furthermore, the effect of metformin as additional therapy on glycaemic control and insulin sensitivity was examined in a randomised placebo-controlled study. Body mass index (BMI) and percentage body fat (%BF) were significantly higher in girls with type 1 diabetes compared to healthy control girls. Mean HbA1c during puberty, but not mean insulin dose, was positively related to BMI at the age of 18 in girls with diabetes. A centralised fat distribution was associated with poor glycaemic control, increased daily dosage of insulin and elevated cholesterol and triglyceride levels. Neither total physical activity nor total energy intake differed between adolescent girls with type 1 diabetes and healthy age-matched control girls. A high dietary fat intake was positively related to gain in %BF in girls with type 1 diabetes. Additional therapy with metformin for three months improved glycaemic control and peripheral insulin sensitivity in adolescents with poorly controlled type 1 diabetes. The improvement in glycaemic control was related to insulin sensitivity at baseline, implying that the most insulin resistant subjects benefited most from the metformin therapy. It is concluded that the excessive weight gain observed in girls with type 1 diabetes is mainly attributable to an increased fat mass and that dietary fat intake is of importance for this gain in body fat. Additional treatment with metformin improves glycaemic control in adolescents with poorly controlled type 1 diabetes.

The process of β-cell destruction that leads to type 1 diabetes (T1D) is incompletely understood and it is believed to be a result of both genetic and environmental factors. Enterovirus (EV) infections of the β-cells have been proposed to be involved, however, the effects of EV infections on human β-cells have been little investigated. This thesis summarises studies of three different Coxsackie B4 virus strains that have previously been shown to infect human islets. The effects of infections with these EV were studied in vitro in human islets and in a rat insulin-producing cell line. In addition, a pilot study was performed on isolated human islets to investigate the ability to treat such infections with an antiviral compound. It was found that one of the virus strains replicated in human β-cells without affecting their main function for at least seven days, which in vivo may increase a virus’s ability to persist in islets. Nitric oxide was induced by synthetic dsRNA, poly(IC), but not by viral dsRNA in rat insulinoma cells in the presence of IFN-γ, suggesting that this mediator is not induced by EV infection in β-cells and that poly(IC) does not mimic an EV infection in this respect. All three virus strains were able to induce production of the T-cell chemoattractant interferon-γ-inducible protein 10 (IP-10) during infection of human islets, suggesting that an EV infection of the islets might trigger insulitis in vivo. Antiviral treatment was feasible in human islets, but one strain was resistant to the antiviral compound used in this study. To conclude, a potential mechanism is suggested for the involvement of EV infections in T1D. If EV infections induce IP-10 production in human islet cells in vivo, they might recruit immune cells to the islets. Together with viral persistence and/or virus-induced β-cell damage, this might trigger further immune-mediated β-cell destruction in vivo.

Sammanfattning Syftet med föreliggande arbete var att studera förekomsten av felaktiga läkemedelsordinationer på en pediatrisk avdelning. Metoden bestod i journalgranskning av läkemedelsordinationer av inskrivna patienter (n = 94) under två månader, 2012. Journalgranskningen utfördes i journaldatabasen Cosmic och omfattade 543 läkemedelsordinationer vilka granskades utifrån flertalet variabler. Resultatet visade att 174 av 543 (32 %) ordinationslistor var felaktiga. Läkemedelsnamn samt hänvisning till speciallista var angivet i samtliga ordinationer. Läkemedelsform var angivet i majoriteten av läkemedelsordinationerna. Styrka var ej angivet i 1 %, dos var ej angivet i 2 %, administrationssätt var felaktigt angivet i 6 % och var ej angivet i 9 %, administrationstidpunkt var ej angivet i 2 %. Maxdos för vid behovsläkemedel var ej angivet i 35 % och spädningsschema eller hänvisning till spädningsschema var ej angivet i 10 % av läkemedelsordinationerna. Slutsatsen visar att de vanligaste felaktigheterna bestod i administrationssätt, maxdos för vid behovsläkemedel samt spädningsschema eller hänvisning till spädningsschema. Alla felaktigheter i läkemedelsordinationen har påverkan på arbetssituationen för sjuksköterskan i såväl handhavandet av läkemedel, tidsåtgång samt resurser inom vården, vilket äventyrar patientsäkerheten. / Abstract The aim of the study was to investigate the incidence of drug prescription errors at a pediatric ward facility. The method used consisted of medical record review of drug prescription errors of enrolled patients (n = 94) for two months during 2012. Medical record review was performed and included 543 drug prescriptions, which were evaluated. The results showed that 174 of 543 (32 %) of prescription lists were incorrect, based on information given with the medication. The study found that drug name and reference to the specialist were always provided. However, errors included: dosage form not specified in 0.4%, strength was not specified in 1.1%, dose was not specified in 1.6%, route of administration was incorrectly stated in 5.9% and was not specified in 8.8%, administration time was not specified in 1.7%. Maximum dose for range order was not specified in 34.9% and dilution scheme or reference to dilution scheme was not specified in 9.6%. The conclusion of the study was that the most common prescription errors consisted of route of administration, the maximum dose if necessary drugs and dilution scheme or reference to dilution scheme. Prescription errors have effects in the workplace for nurses in the administration of drugs, which threatens patient safety.

Parents experience many stressful situations when their child is ill and needs medical care, irrespective of the child’s age, diagnosis or the severity of the illness. Poor sleep quality and negative mood decrease the parents’ ability to sustain attention and focus, to care for their ill child, and to cope with the challenges they face. The overall aim of this thesis was to evaluate sleep, mood, cortisol response, and sense of coherence (SOC) in parents caring for children in need of medical care, and to identify factors that may influence parents’ sleep. This thesis includes four original studies; two of these are quantitative, prospective, descriptive and comparative studies including parents (n=82) accommodated in six pediatric wards with their ill child, using questionnaires and sleep logs to measure sleep, mood and SOC, and saliva cortisol to measure cortisol response. A follow-up was performed four weeks later at home, after hospital discharge. The other two studies are qualitative, inductive and explorative interview studies, including parents (n=12) staying overnight with their preterm and/or ill infant in three neonatal intensive care units, and parents (n=15) with a child receiving hospital-based home care in two pediatric outpatient clinics. The interviews were analyzed with a phenomenographic method. Being together with one’s family seems beneficial for sleep and may decrease stress. The ability to stay with the child, in the hospital or at home, was highly appreciated by the parents. When caring for a child with illness, parents’ sleep quality was sufficient in the hospital; however, sleep quality improved further (p&lt;0.05) at home after discharge. The parents reported frequent nocturnal awakenings in the hospital caused by the child, medical treatment and hospital staff. Concern and anxiety about the child’s health, and uncertainty about the future were stressors affecting the parents’ sleep and mood negatively. The parents had lower (p=0.01) morning awakening cortisol levels in the pediatric ward compared to at home, and parents accommodated for more than one night had lower (p&lt;0.05) post-awakening cortisol levels compared to parents staying their first night. The findings of this thesis conclude that being together as a family is important for the parents’ sleep. The ability to be accommodated in the hospital and gather the family around the child may have given the parents time for relaxation and recovery, that in turn may lead to a less stressful hospital stay. When it is beneficial for the child, the whole family should be included in the pediatric care. Moreover, pediatric nurses must acknowledge parents’ sleep, in hospital and at home. Medical treatment and care at night should be scheduled and sleep promoted for the parents in order to maintain health and well-being in the family. / <p>The electronic version of the thesis is a corrected version of the printed thesis.</p><p>This thesis has also been funded by <em>Barnklinikens 60-årsfond, Filip SchelinsStiftelse, Riksföreningen för barnsjuksköterskor</em> and <em>Synskadades Riksförbund (Lyckopenningen)</em>.</p>

Background: Hereditary angioedema (HAE) due to C1-inhibitor deficiency, type I and II, is a rare disease with an estimated prevalence of 1/50,000. Angioedema in the larynx can be life threatening and angioedema in the abdomen and skin can give severe and disabling pain. Data on patients with HAE in Sweden were scarce before our study. Aim: To study the prevalence of HAE, and to investigate clinical manifestations, treatments, and Health-Related Quality of Life (HR-QoL) in adults and children in Sweden. Method: In studies, I and II, all patients received a written questionnaire followed by a phone interview with questions about clinical manifestations, medication, sick leave and QoL. In study III the patients completed EuroQol 5 Dimensions 5 Levels (EQ-5D-5L) questionnaires for both the attack-free state (EQ5D today), and the last HAE attack (EQ5D attack). Questions were also asked about sick-leave. In study IV all adults received questionnaires with EQ-5D-5L and RAND-36, Angioedema Quality of Life instrument (AE-QoL), and Angioedema Activity Score (AAS) form, and questionnaires on sick leave and prophylactic medication. Results: We identified 146 patients, 110 adults and 36 children with HAE, type I (n=136) or II (n=10), giving a minimal HAE prevalence of 1.54/100,000. For adults, the median age at onset of symptoms was 12 years and median age at diagnosis was 22 years. Median age at onset of symptoms for children was 4 years and at diagnosis 3 years. During the previous year, 47% of adults experienced at least 12 attacks, 21% 4-11 attacks, 11% 1-3 attacks, while 22% were asymptomatic. For children, the corresponding figures were about the same. The median number of attacks in those having attacks was 14 in adults and 6 in children last year. Adult females reported on average 19 attacks the previous year versus nine for males. Irrespective of location nine out of 10 reported pain. Trigger factors were experienced in 95 % of adults and 74 % of children. Plasma-derived C1-inhibitor concentrate (pdC1INH) had a very good effect on acute attacks. Long-term prophylaxis with androgens and pdC1INH reduced the annual attack frequency by more than 50 %. Of the children’s parents, 73% had been on parental leave to care for the child due to HAE symptoms. Health and QoL were generally rated as good. In study III 103 of 139 responded and reported an EQ5D today score that was significantly higher than the EQ5D attack score. Attack frequency had a negative effect on EQ5D today. Children had significantly higher EQ-5D-5L than adults. Forty four percent had been absent from work or school during the latest attack. In study IV 64 of 133 adults responded. The most affected HR-QoL dimensions in EQ-5D-5L were pain/discomfort and anxiety/depression, in RAND-36 energy/fatigue, general health, health transition, pain, and in AE-QoL fears/shame and fatigue/mood. Females had significantly lower HR-QoL in RAND-36 for general health and energy/fatigue. There was an association between AAS and EQ-5D-5L/RAND-36 (except physical function) /AEQoL. There was no significant difference in HR-QoL in patients with and without prophylactic medication. Conclusion: The minimal prevalence of HAE type I and II in Sweden is 1.54/100,000. Median age at onset was 12 years. Adult females had twice as many attacks as males, adults had also twice as many attacks as children. For acute treatment, pdC1INH had a very good effect. For long term prophylaxis, androgens and pdC1INH had good effect. The most affected HR-QoL dimensions in EQ-5D-5L were pain/discomfort and anxiety/ depression, in RAND-36 energy/fatigue, general health, health transition and pain, and in AE-QoL fears/shame and fatigue/mood. Children reported better HR-QoL than adults. AE-QoL is more disease-specific in HAE than the generic instruments EQ-5D-5L and RAND-36. However, the latter highlights the pain aspect, whereas AE-QoL does not. Patients with high disease activity should thus be considered for more intensive treatment to improve their HR-QoL.

Ätproblem hos barn är relativt vanliga och existerar både hos i övrigt friska barn och hos barn med andra sjukdomar och diagnoser. I vissa fall är ätproblemen så allvarliga att de leder till malnutrition. Ofta delas ätproblem in i kategorier beroende på om man tycker sig se en medicinsk orsak eller inte, man skiljer därmed på organiska och icke-organiska problem. Detta arbete fokuserar främst på det som i litteraturen brukar kallas matvägran. Syftet var att belysa området i stort genom att presentera och diskutera aktuell litteratur och forskning om matvägran samt att kritiskt granska olika förklarings-modeller och begrepp. Tre fall av barn med matvägran beskrivs också. Beskrivningarna är baserade på information som lämnats av barnens mödrar i intervjuer och syftar till att beskriva hur naturalförloppet vid matvägran kan se ut samt att undersöka föräldrarnas attityder och känslor kring problemet i sig och kring vårdkontakter. Gemensamma drag var bland andra att barnen haft problem med att äta redan från början och att de alla kräkts frekvent. Mödrarna i de tre fallen beskriver också att de är besvikna över vården av deras barn. Genomgången av etiologi och orsaksteorier pekar mot att matvägran sannolikt är en komplex samverkan mellan en rad olika fysiologiska, psykologiska och miljömässiga faktorer. Att kalla besvären antingen organiska eller icke-organiska kan vara missvisande. Huruvida barnet uppvisar en ovilja eller aversion mot att äta borde vara avgörande för val av behandling och behandlingen bör utformas så att barnets integritet respekteras. / Feeding problems in children are common and exist both in otherwise healthy children and in children with medical conditions. In some cases the feeding problems are severe enough to cause malnutrition. A distinction is often made between organic feeding problems, which are thought to be caused by a medical condition and non-organic problems, where no obvious medical reason can be found. This study was primarily focused on what is referred to as food refusal. The aim of the study was to illuminate the area by presenting and discussing current research as well as critically view common terminology and theories. Three case studies of children with food refusal are also posed. The descriptions are based on information extracted from interviews of their mothers and aim to describe how the natural course of food refusal can present itself as well as to explore parental attitudes and feelings around the problem itself and around contacts with the health care system. Some of the common denominators were that the children all exhibited feeding problems from the beginning and that they have suffered frequent vomiting. The mothers have been disappointed with the care that their children have received. The review of etiology and theories points towards food refusal being a complex interplay between physiological, psychological and environmental factors. To label the problem as being either organic or non-organic can be misleading. Weather the child exhibits an aversion or unwillingness to eat should be an important aspect in choosing treatment form and respecting the child´s integrity should be a priority in treatment.

Adolescents with type 1 diabetes (T1DM) are given nutritional education, but the knowledge about their adherence to the food recommendations and associations between dietary intake and metabolic control is poor. Gastrointestinal symptoms are more prevalent in adults with T1DM than in healthy controls, which may be due to disturbed gastrointestinal motility. The meal content affects the gastric emptying rate and the postprandial glycaemia in healthy adults and adults with type 2 diabetes. Meal ingestion also elicits several postprandial hormonal changes of importance for gastrointestinal motility and glycaemia. Eating disorders are more prevalent in young females with T1DM than in healthy females, and are associated with poor metabolic control. The prevalence of eating disorders in adolescent boys with T1DM is not known.  This thesis focuses on eating and gastrointestinal function in adolescents with T1DM. Three population-based, cross-sectional studies demonstrated that adolescents with T1DM consume healthy foods more often and have a more regular meal pattern than age- and sex-matched controls. Yet both boys and girls are heavier than controls. The intake of saturated fat is higher and the intake of fibre is lower than recommended in adolescents with T1DM. Patients with poor metabolic control consume more fat and less carbohydrates than patients with better metabolic control. Gastrointestinal symptoms are common in adolescents with T1DM, but the prevalence is not increased compared with controls. Gastrointestinal symptoms in patients are associated with female gender, daily cigarette smoking, long duration of diabetes, poor metabolic control during the past year, and an irregular meal pattern. Adolescent boys with T1DM are heavier and have higher drive for thinness than healthy boys, but do not differ from them in scales measuring psychopathology associated with eating disorders.   In a randomized, cross-over study, we found that a meal with a high fat and energy content reduces the initial (0–2 hours) postprandial glycaemic response and delays gastric emptying in adolescents with T1DM given a fixed prandial insulin dose compared with a low-fat meal. The glycaemic response is significantly associated with the gastric emptying rate. Both a high- and a low-fat meal increase the postprandial concentrations of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) and suppress the postprandial ghrelin levels in adolescents with T1DM. The postprandial changes of these hormones are more pronounced after the high-fat meal. Insulin-like growth factor binding-protein (IGFBP) –1 concentrations decrease after insulin administration irrespective of meal ingestion. The GLP-1 response is negatively associated with the gastric emptying rate. The fasting ghrelin levels are negatively associated with the postprandial glycaemic response, and the fasting IGFBP-1 levels are positively associated with the fasting glucose levels.  We conclude that nutritional education to adolescents with T1DM should focus more on energy intake and expenditure to prevent and treat weight gain. It should also focus on fat quality and fibre intake to reduce the risk of macrovascular complications and improve glycaemia. Gastrointestinal symptoms in adolescents with T1DM should be investigated and treated as in other people irrespective of having diabetes. However, adolescents with long duration of diabetes, poor metabolic control, and symptoms from the upper gut should have their gastric emptying rate examined during euglycaemia. There may be an increased risk for development of eating disorders in adolescent males with T1DM since they are heavier than healthy boys and have higher drive for thinness. This should be investigated in future, larger studies.  For the first time, we showed that a fat-rich meal delays gastric emptying and reduces the initial glycaemic response in patients with T1DM. The action profile of the prandial insulin dose to a fat-rich meal may need to be postponed and prolonged compared with the profile to a low-fat meal to reach postprandial normoglycaemia. Circulating insulin levels affect postprandial GIP, GLP-1, and ghrelin, but not IGFBP-1, responses less than the meal content. The pronounced GIP-response to a fat- and energy-rich meal may promote adiposity, since GIP stimulates lipogenesis. Such an effect would be disadvantageous for adolescents with T1DM since they already have increased body fat mass and higher weights compared with healthy adolescents. Adolescents with T1DM may have subnormal postprandial ghrelin suppression, which may be due to their increased insulin resistance or elevated growth hormone levels. This needs to be investigated in future, controlled studies.