<p>Morbidity of asthma has increased over the world. The reasons for this increase have remained unclear. Studies in children have reported considerable East-West difference in the prevalence of atopy and respiratory allergies.</p><p>The aim of this thesis was to compare the prevalence and risk factors of respi-ratory symptoms, atopic sensitisation and bronchial hyperresponsiveness (BHR) in young adults in Estonia and Sweden. </p><p>Following the protocol of the European Community Respiratory Health Survey (ECRHS), two random population samples, 3000 from Tartu, Estonia, and 3600 from Uppsala, Sweden were investigated with postal questionnaires. Random sub samples and subjects with asthma-like complaints were subsequently interviewed, BHR was tested and serum samples analysed for total and specific IgE and eosinophil cationic protein (ECP). In a separate study two methacholine challenge methods, using either Spira Elektro2 or Mefar MB3 as dosimeters, were compared on 28 mild to moderate asthma patients.</p><p>Symptoms of asthma and hay fever were less common in Esto-nia than in Sweden, while respiratory symptoms in general were more common in Estonia. The prevalence of BHR was high and the prevalence of atopy and the levels of serum ECP were low in Tartu. The differences between the two centres in the prevalence of atopy and allergic rhinitis diminished with age, indicating a probable cohort effect. Current smoking was a dominant risk factor for BHR and for all respiratory symptoms, except attacks of asthma, both in Tartu and Uppsala. There was some difference between risk factors for BHR and atopy between Tartu and Uppsala, mostly of social and environmental origin. The low prevalence of hay fever and asthma in Tartu seemed to be partly explained by a lack of awareness of atopy and allergic diseases in the Estonian society. The estimated cumulative dose causing a 20% fall in FEV₁ was smaller and the decline of FEV₁ /log(dose) curve steeper, using the Spira, compared to the Mefar protocol.</p>

Morbidity of asthma has increased over the world. The reasons for this increase have remained unclear. Studies in children have reported considerable East-West difference in the prevalence of atopy and respiratory allergies. The aim of this thesis was to compare the prevalence and risk factors of respi-ratory symptoms, atopic sensitisation and bronchial hyperresponsiveness (BHR) in young adults in Estonia and Sweden. Following the protocol of the European Community Respiratory Health Survey (ECRHS), two random population samples, 3000 from Tartu, Estonia, and 3600 from Uppsala, Sweden were investigated with postal questionnaires. Random sub samples and subjects with asthma-like complaints were subsequently interviewed, BHR was tested and serum samples analysed for total and specific IgE and eosinophil cationic protein (ECP). In a separate study two methacholine challenge methods, using either Spira Elektro2 or Mefar MB3 as dosimeters, were compared on 28 mild to moderate asthma patients. Symptoms of asthma and hay fever were less common in Esto-nia than in Sweden, while respiratory symptoms in general were more common in Estonia. The prevalence of BHR was high and the prevalence of atopy and the levels of serum ECP were low in Tartu. The differences between the two centres in the prevalence of atopy and allergic rhinitis diminished with age, indicating a probable cohort effect. Current smoking was a dominant risk factor for BHR and for all respiratory symptoms, except attacks of asthma, both in Tartu and Uppsala. There was some difference between risk factors for BHR and atopy between Tartu and Uppsala, mostly of social and environmental origin. The low prevalence of hay fever and asthma in Tartu seemed to be partly explained by a lack of awareness of atopy and allergic diseases in the Estonian society. The estimated cumulative dose causing a 20% fall in FEV1 was smaller and the decline of FEV1 /log(dose) curve steeper, using the Spira, compared to the Mefar protocol.

Background: The reasons why some individuals become IgE-sensitised and allergic are largely unknown, though genetic- and early life environmental factors seem to be of importance. Objective: The overall aim of this thesis was to investigate the relationship between IgE-sensitisation and allergic disease, viral infections, genetic markers and early life cytokines. Results: IgE-sensitised children were found to have reduced numbers of IL-12 producing cord blood mononuclear cells (CBMC), whereas children diagnosed with eczema were found to have reduced numbers of IFN-γ producing CBMC. When dividing the children into early onset of IgE-sensitisation and late onset of IgE-sensitisation we found that the children with an early onset had low numbers of PHA-induced IL-4, IL-12 and IFN-γ secreting CBMC. At the age of two there was a general exacerbation of cytokine responses in the IgE-sensitised children, and the results were similar for the children with early onset IgE-sensitisation. Children with a late onset IgE-sensitisation were more similar to the non-sensitised children, but with a specific increase in the response to cat allergen (IL-4 and IFN-γ). The mothers of IgE-sensitised children, were just as their children, found to have an exaggerated cytokine response as compared to mothers of non-sensitised children. Maternal responses correlated well to the responses seen in the child, though the samples were taken two years after delivery. Cytomegalovirus (CMV) infection in early life was associated to reduced numbers of IL-4, and increased numbers of IFN-γ producing cells at the age of two. No association between CMV seropositivity and IgE-sensitisation was seen. Epstein-Barr virus (EBV) infection, on the other hand, was inversely correlated with IgE –sensitisation, whereas no statistically significant association to cytokine production could be seen. We also showed that the IL12B 1188 C-allele was associated to having a positive skin prick test at the age of two. The rare alleles of the three SNPs investigated (IL12B 1188C, IL12RB1132C and IRF1 1688A) were all associated to low IL-12 production at birth. Conclusions: Our results indicate that allergic diseases are complex traits, and that both the genetic and the cytokine background differ between the different allergic diseases. We can also conclude that the time of onset seem to play a role when investigating IgE-sensitisation, and that perhaps early and late onset IgE-sensitisation have partly different causes. CMV and EBV infection early in life are associated to a protective cytokine profile and to protection from IgE-sensitisation, respectively, again indicating the heterogeneity and the complexity of allergic diseases.

Nickel stands out as the main cause of contact allergy in both children and adults, which has given rise to concern and the introduction of regulations by official bodies. Today´s youths are frequently exposed to body piercing and orthodontic treatment. Changes in youth lifestyle practices are also likely to influence nickel exposure and thus, the occurrence of nickel allergy. However, against patient and parental concern regarding nickel exposure to orthodontic appliances, often evoked by allergies following piercing, stand results from studies indicating that early orthodontic appliance treatment may reduce, rather than increase, prevalence of nickel allergy; a finding that has been suggested to result from tolerance induction by early exposure to nickel via the oral route. The objective of the present thesis was to investigate the association between nickel allergy and exposure to different orthodontic appliances and lifestyle, in particular piercing, as well as to study nickel release from orthodontic appliances into the oral cavity. Furthermore, one objective was to establish baseline prevalence data of nickel allergy in a Swedish adolescent population. Data was generated from a cross-sectional survey, in which about 6000 youths completed a questionnaire and almost 4500 of these were patch-tested for contact allergy. Information on exposure to orthodontic appliances was verified by dental records, whilst nickel content in saliva and dental biofilm was measured in a clinical study. Questionnaire data demonstrated a reduced risk of nickel allergy when orthodontic treatment preceded piercing (OR 0.5; 95 % CI 0.3-0.8) and similar results were found for data verified from dental records, however statistical significance was lost when adjusting for background factors (OR 0.6, 95 % CI 0.4-1.0). Exposure to full fixed appliances with NiTi-containing alloys, as well as a pooled ‘high nickel-releasing’ appliance group prior to piercing correlated with a significantly reduced risk of nickel allergy and a trend towards a reduced risk with exposure duration. Nickel could also be found in significantly higher concentrations from dental plaque samples, but not saliva samples, in orthodontic patients who were well into treatment compared to patients who had not been exposed to orthodontic appliances. The effect was not found to be due to differences in estimated dietary nickel intake between the two groups. Significantly more girls than boys (13.3 % versus 2.5 %) were found to be patch-test positive to nickel. Positive nickel tests were also most prevalent in occupational programmes and least prevalent in natural science programmes, indicating differences in lifestyle and exposure to nickel. Dropout from testing was handled using a missing-value analysis. This internal validation showed that our results overestimated the occurrence of nickel allergy to a minor degree. More girls than boys reported piercing, vegetarian/vegan diet, and smoking practices, whereas an interesting shift in tattooing prevalence was observed with a larger proportion of girls reporting this practice compared to boys. Sex, number of piercings, smoking and orthodontic appliance treatment prior to piercing were found to influence weighted risk estimates of nickel allergy. To conclude, although orthodontic patients are exposed to nickel intraorally, we found no increased risk of sensitising adolescents to nickel by the use of oral orthodontic appliances. On the contrary, early orthodontic treatment preceding piercing reduced the risk of nickel allergy by a factor of 1.5-2.0. This reduced risk appears to be associated with estimated nickel release of the appliance and duration of treatment, in all supporting a hypothesised induction of immunological tolerance via oral administration of nickel. Our study also showed a strong association between lifestyle and nickel allergy. Although there have been changes in lifestyle over time, as indicated by the strong shift in tattooing practices, no large change in nickel allergy prevalence was found compared with previous Swedish data. Our data will serve as a baseline for future studies of the effect of nickel exposure regulations, such as the Nickel Directive, and for studies of lifestyle changes and their effects on nickel allergy.

The increasing prevalence of allergic diseases in affluent societies has been associated with changes in microbial exposure early in life and a less diverse gut flora. The objective of this thesis was to assess the development of allergic sensitisation and symptoms during the first four years of life in a non-selected birth cohort in relation to environmental factors, family history, gut microbiota and salivary IgA antibodies. The cohort comprised all 1,228 infants living in a Swedish county who were born over a one-year period. The parents replied to questionnaires, and 817 children (67 %) were skin prick tested both at 1 and 4 years of age. Saliva (n=279), faecal (n=139) and blood (n=253) samples were collected at 1 year of age from children with a positive skin prick test at 1 year and from a sample of children with a negative skin prick test. Faecal samples were also obtained from 53 children at 4 years of age. Dog keeping during infancy was associated with a decreased risk of sensitisation to pollen and late-onset wheezing at age 4, and the reduced odds ratios persisted after adjustment for heredity and avoidance measures, OR 0.3, 95% CI 0.1-0.9 and OR 0.5, 95% CI 0.2-1.0, respectively. In contrast, early dog keeping was associated with an increased risk of earlyonset transient wheezing but only in children with parental asthma (OR 2,8, 95% CI 1.3-6.4). Levels of short chain fatty acids (SCFAs) in faeces were assessed both at 1 and 4 years of age and related to the development of sensitisation and symptoms. The levels of acetic (p&lt;.01) and propionic (p&lt;.01) acids decreased from one to four years of age, whereas valeric acid (p&lt;.001) increased which is in line with a more complex gut microbiota with age. Allergic children, compared with non-allergic children, had lower levels of i-butyric, i-valeric and valeric acid in faeces both at 1 and 4 years of age. Low levels of secretory IgA (SIgA) in saliva were associated with wheezing but only in sensitised children. In children with positive SPT to at least one allergen both at 1 and 4 years of age and in children with circulating IgE antibodies to egg or cat at one year of age, those who developed late-onset wheezing had lower levels of SIgA than those who did not, p=.04 and p=.02 respectively. Of 9 children with levels of SIgA in the upper quartile and persistent sensitisation, none developed wheezing, compared with 10/20 children with lower levels, (p=. 01). Having older siblings, more than three infections during infancy, at least one smoking parent and male gender were all associated with high levels (in the upper quartile) of total IgA and SIgA. The findings in this thesis indicate that the microbial load early in life could affect the development of allergy. A functional assessment of the gut flora demonstrated differences between allergic and non-allergic children both at 1 and 4 years of age. Salivary IgA was associated with infections during infancy, and high levels of secretory IgA protected from symptoms in sensitised children. Finally, dog keeping in infancy may offer protection from allergy, but the mechanism is uncertain.

This study investigated two hypotheses. First, that chronic cocaine treatment would mimic the changes in breathing that are associated with ventilatory acclimatisation to chronic hypoxia (VAH). Second, that pre-treatment with a hypoxic stressor would bring about cross-sensitisation to cocaine. To address the first hypothesis, rats were exposed to either chronically hypoxic or chronically normoxic conditions and treated with either cocaine or saline for a 14 day period. Following this period, acute breathing trials were performed to measure resting ventilation and ventilatory chemoreflexes. The results demonstrated that chronic cocaine treatment did not induce the changes in breathing associated with VAH. To address the second hypothesis rats were exposed to a hypoxic stressor for 10 days (either intermittent hypoxia or chronic hypoxia) after which cocaine sensitisation was measured via locomotor sensitisation trials. The results demonstrated that cross-sensitisation between a hypoxic stress and cocaine was observed for intermittent but not chronic hypoxia.

This study investigated two hypotheses. First, that chronic cocaine treatment would mimic the changes in breathing that are associated with ventilatory acclimatisation to chronic hypoxia (VAH). Second, that pre-treatment with a hypoxic stressor would bring about cross-sensitisation to cocaine. To address the first hypothesis, rats were exposed to either chronically hypoxic or chronically normoxic conditions and treated with either cocaine or saline for a 14 day period. Following this period, acute breathing trials were performed to measure resting ventilation and ventilatory chemoreflexes. The results demonstrated that chronic cocaine treatment did not induce the changes in breathing associated with VAH. To address the second hypothesis rats were exposed to a hypoxic stressor for 10 days (either intermittent hypoxia or chronic hypoxia) after which cocaine sensitisation was measured via locomotor sensitisation trials. The results demonstrated that cross-sensitisation between a hypoxic stress and cocaine was observed for intermittent but not chronic hypoxia.

N-methyl-D-asparate (NMDA) receptors located within the basolateral complex of the amygdala are required for the consolidation and expression of Pavlovian conditioned fear. The events downstream of receptor activation that mediate these processes are not well defined. An intermediate step that may be of significance is the synthesis of the gas nitric oxide (NO). Nitric oxide is synthesised as a result of NMDA receptor activation and acts as an unconventional neurotransmitter freely diffusing across cell membranes interacting with its targets in a non-synaptic manner. The targets of NO include cellular components that play significant roles during the consolidation of conditioned fear and the neurotransmission associated with its expression. This implies that NO may be an important intermediary of NMDA receptor activation and both these processes. The current study sought to examine this possibility using fear potentiated startle to examine the expression of learned fear. Three experiments were conducted, fifty rats received intra-BSC microinfusions of the global nitric oxide synthase inhibitor L-NAME either prior to fear conditioning, fear testing, or examination of the shock sensitization of the acoustic startle affect. The results indicated that NO was indeed required for both the consolidation and expression of learned fear, whereas it was not required for shock enhanced startle responding. This study provides new information about the sub-cellular basis of conditioned fear, and highlights the pivotal role played by NO in processes associated with conditioned fear.

The neuronal substrates underlying aspects of comorbidity in brain disease states may be described over psychiatric and neurologic conditions that include affective disorders, cognitive disorders, schizophrenia, obsessive-compulsive disorder, substance abuse disorders as well as the neurodegenerative disorders. Regional and circuitry analyses of biogenic amine systems that are implicated in neural and behavioural pathologies are elucidated using neuroimaging, electrophysiological, neurochemical, neuropharmacological and neurobehavioural methods that present demonstrations of the neuropathological phenomena, such as behavioural sensitisation, cognitive impairments, maladaptive reactions to environmental stress and serious motor deficits. Considerations of neuronal alterations that may or may not be associated with behavioural abnormalities examine differentially the implications of discrete areas within brains that have been assigned functional significance; in the case of the frontal lobes, differential deficits of ventromedial and dorsolateral prefrontal cortex may be associated with different aspects of cognition, affect, remission or response to medication thereby imparting a varying aspect to any investigation of comorbidity.

The localised corrosion behaviour of various grades of Austenitic Stainless Steels has been demonstrated by optical and electron microscopy. The effect of sensitisation upon subsequent corrosive attack has been investigated. A theoretical model based upon thermodynamic and kinetic considerations has been proposed to account for the observed experimental results. / Thesis / Master of Engineering (ME)