Adolescensutvecklingen är en känslig period, då övergången från att vara ett beroende barn till att bli en självständig vuxen skall äga rum. Under denna kritiska process sker identitetsutveckling och strävan efter att vara oberoende föräldrar ökar. År 2013 rapporterades att cirka 50000 personer i Sverige har typ 1 diabetes mellitus (T1DM) och statistik pekar på en ständig ökning av sjukdomen. T1DM är en ämnesomsättningssjukdom som kännetecknas av brist på hormonet insulin. Sjukdomen behandlas med insulin, kost och motion och kräver dessutom regelbundenhet och daglig egenvård. Syftet med studien var att identifiera hälsorelaterade utmaningar med T1DM under adolescensutvecklingen, ur ett personperspektiv. Studien är utförd som en litteraturstudie där 13 vetenskapliga artiklar har granskats och bearbetats. Resultatet visar att T1DM under adolescensutvecklingen medför speciella utmaningar och problematik kring föräldrarelationen, vikten av kunskap och stöd samt behovet av att vara som alla andra. Vidare forskning bör fokusera på föräldrars samt hälso- och sjukvårdspersonals perspektiv kring T1DM under adolescensutvecklingen, för att få ett helhetsperspektiv och kunna stödja den drabbade ungdomen på bästa sätt. / The adolescence is a sensitive period with the transition from being a dependent child to becoming an independent adult. During this critical process ones identity develops and the desire to be self-sustaining without parents increases. In 2013 it was reported that approximately 50 000 people in Sweden have type 1 diabetes mellitus (T1DM) and statistics point to a steady increase of the disease. T1DM is a metabolic disease characterized by a lack of the hormone insulin. The disease is treated with insulin, diet and exercise and also requires regularity and daily self-care. The purpose of this study was to identify health related challenges with T1DM during the period of adolescence, from a person perspective. This is a literature study in which 13 scientific articles have been reviewed and processed. The result shows that T1DM during the period of adolescence poses special challenges and problems relating to the parental relationship, the importance of knowledge and support, and the need to be like everyone else. Further research should focus on the perspectives of both parents and healthcare staff on T1DM during adolescence, to get an overall perspective and be able to assist the affected youth in the best possible way.

Bakgrund: Diabetes typ 1 är en vanlig kronisk sjukdom som oftast drabbar barn. Sverige är ett av de länder som har högst incidens av diabetes typ 1 i världen. Diabetes typ 1 är en sjukdom där egenvården anses vara livsavgörande. Då sjukdomen drabbar barn spelar föräldrars delaktighet i egenvården en central roll. Syfte: Syftet med denna studie är att beskriva föräldrars upplevelse av delaktigheten i vården av sitt barn med diabetes typ 1. Metod: Studien är en allmän litteraturstudie, baserad på 10 kvalitativa artiklar. Resultat: Resultatet visade att föräldrar bar ett stort ansvar i vårdandet kring barnet som har diabetes typ 1. Föräldrars upplevelser kring delaktigheten i vårdandet av sitt sjuka barn bestod i olika känslor, tankar och förändringar. Resultatet redovisas i tre kategorier känslomässiga reaktioner, vårdandets påverkan på vardagen och en ny värld. Slutsats: Det är viktigt att belysa föräldrars upplevelser då detta kan bidra till utveckling av den familjefokuserade omvårdnaden. Genom detta kan sjuksköterskan hjälpa familjer att uppnå en god och säker vård för familjerna med barn som har diabetes typ 1. Av studiens resultat dras slutsatsen att det som sjuksköterska är viktigt att söka förståelse för familjens perspektiv. Vilket författarna ser inom detta område vara att förstå relationen mellan barns sjukdom och föräldrars upplevelser. Klinisk Betydelse: En ökad kunskap hos sjuksköterskor i ämnet, bidrar till en bättre vård där familjefokuserad omvårdnad uppmärksammas i större uträkning. / Background: Diabetes type 1 is one of the most common chronic illness effecting children. Sweden is one of the countries in the world with the highest incident of diabetes type 1. Diabetes type 1 is a disease when self-care plays a life effecting part. As the disease often affects children the parents’ participation in the self-care play a central part. Aim: The aim of this study is to describe parents’ experience of participating in nursing for their child with diabetes type 1. Method: This study is regular literatures study, based on 10 qualitative articles. Results: The result shows that parents’ carried a huge responsibility regarding nursing for the child with diabetes type 1. Parents’ experience regarding participating in nursing for their child consisted in different feelings, thoughts and changes. The result is presented in three categories emotional reactions, nursing affecting the everyday life and a new world. Conclusions: It’s important to highlight parents experience as it can contribute to developing family nursing. Through this the nurse can help the family to achieve a god and safe care for the family having a child with diabetes type 1. The result off this study concludes the important of seeking understanding for the patients’ perspective, by the nurse. Which the author of this study sees, in its context meaning understanding the relationship between children’s disease and parents’ experience. Relevance to clinical practice: Increased knowledge by the nurse in the subject will contribute to better care, where family nursing is in larger computation.

The Angiotensin II Type 1 (AT1) receptor is the main receptor responsible for the effects of the renin-angiotensin system, and its expression pattern is altered in several diseases. [11C]Methyl-Losartan has been developed based on the clinically used AT1 receptor antagonist Losartan. The aim of this work is to characterize the pharmacokinetics, repeatability and reliability of measurements, binding specificity and selectivity of [11C]Methyl-Losartan in rats using in vivo small animal positron emission tomography (PET) imaging, ex vivo biodistribution and in vitro autoradiography methods. Also, we aim to measure the presence of metabolites in the kidney and plasma using high-performance liquid chromatography. We have demonstrated in vivo that [11C]Methyl-Losartan is taken up in the AT1 receptor-rich kidneys and that it is displaceable by selective AT1 receptor antagonists. Using ex vivo biodistribution, we have confirmed these results and demonstrated that [11C]Methyl-Losartan binds selectively to the AT1 receptor over the AT2, Mas and β-adrenergic receptors. In vitro autoradiography results confirmed these renal binding selectivity studies. [11C]Methyl-Losartan was also shown to have one and two C-11 labeled metabolites in the plasma and kidneys, respectively. In conclusion, [11C]Methyl-Losartan is a promising agent for studying the AT1 receptor in rat models with normal and altered AT1 receptor expression using small animal PET imaging.

Aerobic exercise interventions involving individuals with type 1 diabetes have had little positive effect on blood glucose control as reflected by hemoglobin A1c. The few existing interventions involving resistance exercise, either alone or combined with aerobic exercise, while small in sample size, have had better outcomes. The purpose of this research program was to examine the changes in blood glucose levels during activity and for 24 hours post-exercise (as measured by continuous glucose monitoring) when resistance exercise is performed, either on its own or combined with aerobic exercise, as compared to aerobic exercise alone or no exercise. Twelve physically active individuals with type 1 diabetes performed 5 separate exercise sessions in random order separated by at least five days: 1) no exercise/control; 2) aerobic exercise (45 minutes of treadmill running at 60% VO2peak); 3) resistance exercise (45 minutes of weight lifting – 3 sets of 8 repetitions of 7 different exercises); 4) aerobic then resistance exercise (2 and 3 combined with the aerobic exercise first); 5) resistance then aerobic exercise (2 and 3 combined with the resistance exercise first). We found that resistance exercise was associated with a lower risk of hypoglycemia during exercise, less carbohydrate intake during exercise, less post-exercise hyperglycemia and more frequent (but less severe) nocturnal hypoglycemia than aerobic exercise. When aerobic and resistance exercise were combined, performing resistance exercise prior to aerobic exercise (rather than the reverse) resulted in attenuated declines in blood glucose during aerobic exercise, accompanied by a lower need for carbohydrate supplementation during exercise and a trend towards milder post-exercise nocturnal hypoglycemia.

Type 1 diabetes (T1D) is an autoimmune disease whereby the insulin-producing β-cells of the pancreas are destroyed by the immune system, possibly related to an inappropriate immune reaction to dietary antigens and/or microbes in the gut. We previously observed a deficit in gut-resident CD163+ M2 anti-inflammatory macrophages in BioBreeding diabetes-prone (BBdp) rats. Heme oxygenase-1 (HO-1) is the rate-limiting enzyme of the CD163 pathway and through the breakdown of toxic heme releases potent antioxidants. We hypothesized that the treatment of animals with cobalt protoporphyrin (CoPP), an inducer of HO-1 expression, would inhibit development of T1D through modulation of the CD163/HO-1 pathway and increase M2 macrophages. HO-1 expression was significantly increased in the pancreas and gut. T1D incidence was inhibited in CoPP-treated rats and these animals showed an unexpected increase in cells expressing CD68 (an M1 pro-inflammatory macrophage marker) in the pancreas and gut. CoPP induced the expression of cathelicidin anti-microbial peptide (CAMP) in the jejunum, which co-localized with CD163+ (M2) macrophages. KLF4, an M2 macrophage-specific transcription factor, was significantly upregulated in the pancreas and jejunum of CoPP-treated animals and co-localized with CD68 and HO-1 in the pancreas. We conclude that HO-1 induction prevented T1D through modulation of the gut immune system and potential recruitment of a unique population of anti-inflammatory M2 macrophages in the gut and pancreas

Noonan spectrum disorders belong to the RASopathies, a group of clinically related developmental disorders caused by dysregulation of the RAS-MAPK pathway. This thesis describes genetic and clinical investigations of six families with Noonan spectrum disorders. In the first family, the index patient presented with severe Noonan syndrome (NS) and multiple café-au-lait (CAL) spots, while four additional family members displayed multiple CAL spots only. Genetic analysis of four RAS-MAPK genes revealed a de novo PTPN11 mutation and a paternally inherited NF1 mutation, which could explain the atypically severe NS, but not the CAL spots trait in the family. The co-occurrence of two mutations was also present in another patient with a severe/complex NS-like phenotype. Genetic analysis of nine RASopathy-associated genes identified a de novo SHOC2 mutation and a maternally inherited PTPN11 mutation. The latter was also identified in her brother. Both the mother and the brother displayed mild phenotypes of NS. The results from these studies suggest that an additive effect of co-occurring mutations contributes to severe/complex NS phenotypes. The inherent difficulty in diagnosing Noonan spectrum disorders is evident in families with neurofibromatosis-Noonan syndrome (NFNS). An analysis of nine RASopathy-associated genes in a five-generation family with NFNS revealed a novel NF1 mutation in all affected family members. Notably, this family was initially diagnosed with NS and CAL spots. The clinical overlap between NS and NFNS was further demonstrated in three additional NFNS families. An analysis of twelve RASopathy-associated genes revealed three different NF1 mutations, all segregating with the disorder in each family. These mutations have been reported in patients with NF1, but have, to our knowledge, not been associated with NFNS previously. Together, these findings support the notion that NFNS is a variant of NF1. Due to the clinical overlap between NS and NFNS, we propose screening for NF1 mutations in NS patients negative for mutations in NS-associated genes, preferentially when CAL spots are present. In conclusion, this thesis suggests that co-occurrence of mutations or modifying loci in the RAS-MAPK pathway contributes to the clinical variability observed within Noonan spectrum disorders and further demonstrates the importance of accurate genetic diagnosis.

With global freshwater supplies under pressure, viable water reuse methods are being examined to assist in improving water supplies. Municipal effluent is an ideal source for water reclamation as it is consistent in quality and quantity. The health aspects of water reuse have been identified as an issue of concern, in particular the potential presence of enteric viruses. Managed Aquifer Recharge (MAR) is a method that can aid water reclamation by recharging water such as treated effluent into a suitable aquifer. Research into the removal of pathogenic contaminants by natural processes within aquifers, namely the action of autochthonous bacteria, has led to the consideration that MAR could be used to assist in the removal of microbial pathogens. Pathogens have been demonstrated to be removed during residence in groundwater, but the presence of active autochthonous groundwater bacteria are required for significant removal rates to occur. The aim of this research was to investigate the interaction between autochthonous groundwater bacteria (AGB) and the enteroviruses Poliovirus type 1, Coxsackievirus B3 and Adenovirus B41. It was established that these viruses decrease in number in the presence of AGB but the mechanisms causing this decrease are poorly understood. Experiments were designed to examine how the individual AGB caused decay of the viruses. In this study AGB were isolated and tested for their ability in increase the decay of the viruses. It was determined that 27 % (17/63) of the isolated AGB influenced viral decay. The AGB isolates varied in their influence with only 3 out of 17 isolates being able to cause of the decay of both poliovirus and coxsackievirus. Similar variations in decay were observed for adenovirus. Decay times for all three viruses varied amongst the AGB and between the viruses. Experiments were undertaken to characterise the mechanism causing the antiviral activity of four groundwater isolates (1G, 3A, 4B and 9G) under varying conditions and treatments to give insight into the compounds or mechanisms responsible for viral decay. This would indicate whether compounds produced by the AGB responsible for viral decay were closely associated to bacterial cells (perhaps membrane bound), independent of metabolic activity, heat labile or were enzymatic in nature. The influence of enzyme inhibiters and heat treatment indicated that viral degradation is caused by compounds that are enzymatic in nature. As viral numbers were monitored by nucleic acid copy numbers rather than via infectivity assays, the viral protein coats must be the first step in degradation followed by the removal of the viral nucleic acid. This two step process would require both protease and nuclease enzymes to result in loss of viral numbers as measured by RT-PCR/PCR. Further characterisation and identification of these four bacterial isolates was also carried out. Three out of the four isolates were sequenced and analysed using partial 16S rRNA gene sequences to determine their phylogenetic relationships compared to related organisms. Isolate 3A was placed in the order Burkholderiales. Isolate 4B was placed in the family Xanthomonadaceae. Isolate 9G was placed in the family Rhizobiaceae. Isolate 1G was only partially sequenced and preliminary identification placed it in the phylum Bacteriodetes. Understanding of the processes carried out by AGB within an aquifer during MAR using reclaimed waters will aid in increasing the viability of this water reuse process. If important natural processes could be utilised to remediate any potential pathogens, the health concerns with reclaimed waters could be addressed and solved simply through prescribed retention times within the aquifer. Key species of AGB may even be utilised as markers to assess the suitability of an aquifer for MAR.

Hypertension is a major health problem worldwide. In 1999-2000, 29% or 3.6 million Australians aged 25 yrs and over had high blood pressure (> 140 / 90 mmHg) or were on medication for the condition. It is estimated that about one billion of the world’s population has hypertension and that this will increase to 1.56 billion by 2025. Although antihypertensive drugs have been relatively successful in attenuating elevated blood pressure (BP) and in reducing adverse outcomes, control of BP depends on continuation of therapy. Drugs may have undesirable side effects which diminish compliance and BP may be resistant to treatment. Gene transfer approaches may potentially provide a tool to control BP. RNA interference (RNAi) is a new tool for the study of gene function, producing specific down regulation of protein expression. I tested the hypothesis that angiotensin II type 1 receptor (AT1R) inhibition using RNAi technology would result in sustained reduction of blood pressure in the spontaneously hypertensive rat (SHR). To enable in vivo gene delivery into animal models of hypertension, I have developed small interfering RNA (siRNA) inhibition of AT1R mRNA delivered in a DNA plasmid (pPlasRi-AT1R). Transfection of the recombinant plasmid into a mammanlian cell line resulted in strong expression of the transgenes and a significant reduction in the level of AT1R expression. pPlasRi-AT1R plasmid DNA was intravenously injected into adult spontaneously hypertensive rats at 1.5mg/kg. Telemetric blood pressure transducers were implanted into eight month old male SHR for long-term recording of blood pressure. Twenty-four hour intra-arterial blood pressure was measured weekly. After a 2 week control period animals were injected via the tail vein with AT1R DNA plasmid (n=6), control plasmid containing green fluorescent protein (GFP, n=6) or saline (NaCl, n=6)) and followed for 8 weeks. Additional animals were treated with the DNA plasmid or saline and euthanized at 0, 1, 2, 4, 6 and 8 weeks for determination of tissue AT1R expression using RT-PCR. Aims: (i) To develop an accurate radio-telemetry BP recording method in the SHR, (ii) To design rational siRNA sequences and select of methods for effective silencing in vitro, (iii) To measure the expression of DNA delivered RNAi-AT1R plasmid in vitro and in vivo, and (iv) To determine the in vivo effect of systemic delivery of DNA AT1R plasmid on BP. Methods: Continuous 24 h arterial BP was recorded by radio-telemetry using Maclab hardware and a transducer fixed in the abdominal aorta connected to a transmitter in the abdominal cavity. Data was analyzed using software specifically written for the project. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect AT1R transcripts in various tissues following in vivo AT1R gene delivery. BP was monitored weekly for 8 weeks following 1.5 mg DNA delivered RNAi -AT1R plasmid delivery into 8-month-old SHR by tail vein injection. SHR injected with DNA enhanced green fluorescent protein (eGFP) plasmid or saline served as controls. Results: Weekly 24 h BP was successfully recorded for up to 10 weeks. Following transfection with DNA delivered RNAi -AT1R plasmid in vitro, expression of AT1R in transfected cells was determined by western blot, immunofluorescence and flow cytometry. Furthermore, RT-PCR was employed to confirm the AT1R mRNA levels. Following systemic delivery of RNAi-AT1R plasmid into middle-aged SHR, in animals injected with RNAi plasmid control blood pressure (150 +/- 1mmHg) was reduced 1week after injection (145 +/- 0.5 mm Hg, p<0.05) with maximal reduction 4 weeks after injection (127 +/- 1 mmHg, p<0.01). Blood pressure returned to control level by 8 weeks. There was no change in blood pressure in GFP plasmid or saline injected animals. Tissue expression of AT1R in heart, lung, kidney and liver was reduced following AT1R plasmid injection and was associated with reduction in pressure (r=0.99, p<0.05 for each tissue). There were no significant adverse clinical or biochemical effects. AT1R silencing resulted in significant blood pressure reduction in 8 month old male SHR for approximately 2 months. There was a significant decrease in endogenous AT1R gene expression in tissues as determined by RT-PCR. The results suggest that the systemic delivery of siRNA against AT1R mRNA by DNA-based plasmid vector may have potential for gene therapy of hypertension and that further studies with the plasmid packaged into a recombinant DNA vector for a long-lasting siRNA effect are warranted. RNAi technology with inhibition of AT1R offers a potential new paradigm for the management of high blood pressure. Conclusions: Transfection of cells with DNA delivered RNAi -AT1R plasmid resulted in detection of AT1R transcript in transfected cells confirming a silencing effect in vitro. Significant BP reduction was induced in a group of middle-aged SHR following systemic delivery of DNA plasmid incorporating the siRNA against the AT1R gene. This correlated with significant decrease of endogenous AT1R in various tissues which supported the role of the gene therapy approach in producing a reduction in BP. In summary, the thesis lays the foundation for DNA delivered RNAi mediated AT1R gene delivery as a therapeutic strategy for hypertension. Future work should consider the possible benefits of DNA vector driven AT1R shRNA plasmid containing a regulated tissue-selective promoter and explore approaches which might extend the time during which the hypotensive effect is present

Over the past twenty years the incidence of both childhood acute lymphoblastic leukaemia (ALL) and type 1 diabetes have risen in many developed countries, including New Zealand. Although the explanations for this increase and the precise aetiology of both diseases remain unclear, environmental factors are thought to be important. One factor receiving increasing attention is the role of infections introduced through population mixing. However, previous studies on this topic show mixed results and population mixing itself tends to be under-theorised. Furthermore, this issue has not been adequately assessed in New Zealand, a country characterised by high levels of population mobility. In this research, a variety of population mixing measures for small areas in New Zealand were developed. National data on ALL registrations were obtained from the New Zealand Cancer Registry, and regional type 1 diabetes data were obtained from the Canterbury Diabetes Register for the Canterbury Region of the South Island. The analyses were undertaken in three stages. First, standardised incidence ratios of each disease were examined at different geographical and temporal scales, between areas of differing socioeconomic status, and in urban and rural New Zealand. Second, cluster analysis was employed to test for spatial-temporal clustering of the two diseases. Finally, multivariate regression analyses were utilised to investigate the association between each disease and the various measures of population mixing at the area-level. The results reveal similarities in the geographical epidemiology of childhood ALL and type 1 diabetes in New Zealand. The majority of the findings were suggestive of an infectious aetiology for both diseases. In addition, higher incidence of both diseases was observed in areas which increased the most in population mixing over short time periods (6/7 years). Furthermore, raised type 1 diabetes incidence was also associated with high population mixing in early life.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.