The airway surface contains a number of important defense mechanisms to protect against infection. Antimicrobials found in the thin layer of fluid lining the airways, the airway surface liquid (ASL), rapidly kill bacteria. Another defense mechanism, mucociliary transport, propels foreign particles and mucus out of the airways. These and potentially other host defense properties show a dependence on the pH of the ASL. An acidic ASL pH reduces bacterial killing by cationic antimicrobial peptides, and increases ASL viscosity, potentially effecting mucociliary transport. Consequently, an acidic ASL pH can impair airway host defense. An example of a disease where an acidic ASL pH impairs airway host defense, is Cystic Fibrosis (CF). The major cause of morbidity and mortality in CF is airway infections. Humans with CF and the CF pig model develop airway infections. But curiously CF mice are spared. Compared to non-CF, people with CF and CF pigs show an abnormally acidic ASL pH. However, the ASL pH in CF mice is not different to that of non-CF. Thus, we hypothesized that CF mice do not show defects in airway host defense because their ASL pH is not acidic compared to non-CF. As pH is a balance between acid and base secretion, we first determined which HCO3- and H+ secreting proteins contribute to ASL pH and the differences between humans, pigs, and mice. CF is caused by defects in an anion channel, CFTR. We found that in all three species, CFTR secreted HCO3- into the ASL, which was absent when CFTR was defective. To determine how much CFTR is required to rescue ASL pH and host defense properties, we mixed CF and non-CF airway epithelia from newborn pigs in different ratios. HCO3- secretion, ASL pH, and host defense properties showed a direct relationship to CFTR, suggesting that CFTR was the rate-limiting step. As CFTR was limiting, we found that supernormal CFTR expression in a small number of cells could dramatically increase ASL pH, suggesting viral-mediated gene therapy approaches may have benefit for CF. We found that Ca2+ activated Cl- channels also played some role in ASL pH in CF pigs and CF mice. However, as CF pigs develop airway infection, while CF mice do not, this suggested that other factors might be important for differences in ASL pH and consequently the development of disease. To further investigate the determinants of ASL pH, we examined H+ secretion. Humans and pigs showed 6 times more H+ secretion compared to mice. This acidification occurred through the non-gastric H+/K+ ATPase (ATP12A). ATP12A was also much more highly expressed in human and pig airways compared to mice. Blocking ATP12A in human and pig airways increased ASL pH and consequently improved host defense properties such as bacterial killing and ASL viscosity. Conversely, expressing ATP12A in CF mouse airways acidified ASL, impaired defenses, and increased airway bacteria. These findings suggest that ASL pH is a balance between HCO3- and H+ secretion. In humans and pigs lacking CFTR, unchecked H+ secretion by the non-gastric H+/K+ ATPase (ATP12A) acidifies the ASL, which impairs airway host defenses. However, as mouse airways expressed little ATP12A and secrete minimal H+, loss of CFTR does not lead to ASL acidification, protecting CF mice. These findings not only help explain why CF mice are protected from infection, but also nominate ATP12A as a therapeutic target for improving ASL pH and host defense in humans with CF.

Suboptimal growth and nutritional status are problematic for children with cystic fibrosis (CF). Optimal nutrition predicts better lung function and longevity. Daily nutrition therapy for children with CF requires adequate food resources, knowledge of appropriate nutrition and behavior management skills, and confidence in one's ability to correctly apply the necessary skills. The Mountain West Cystic Fibrosis Consortium Questionnaire (MWCFC-Q) was designed as an educational needs assessment for parents of children with CF. The goal was to identify areas of concern that could be targeted for educational intervention to ultimately improve children's growth and nutritional status. Data analyzed from 305 returned surveys included household food security, use of food assistance programs, knowledge of nutrition and general CF therapy, and self-confidence in ability to manage CF care. Questions regarding food security and knowledge of CF nutrition and general therapies were multiple choice. A ten point Likert-type scale was employed for determining confidence around management of CF related issues. Respondents' median accuracy for questions regarding nutrient content of commonly used foods was 71.4% and 57.9% for CF nutrition therapy, respectively. Although overall confidence in CF management was high, scores for confidence in nutrition and behavioral management were significantly lower than for confidence in CF respiratory/medical management and CF Center recommendations. In the second phase of this project, a pilot study using the chronic care model was developed for enhancement of nutrition and behavior management skills of parents of children with CF. Participants attended a series of four classes, each with a short didactic presentation, group activity, and discussion. Important features of this evidence-based educational program included nutrition and behavior management, self-efficacy, problem solving skills, and peer mentoring. A pre-, post-, follow-up, follow-up format was used to evaluate changes in participants' knowledge and self-confidence regarding nutrition and behavioral management. Comparisons were made with responses to the mailed survey using the same questionnaire. Secondary outcomes were changes in the rate of weight gain and growth for participants' children with CF. Participants showed statistically significant improvement in knowledge of nutrition therapy for CF at post-intervention compared with respondents to the mailed survey.

A retrospective chart review was conducted on pediatric patients at the Intermountain Cystic Fibrosis Center who had a percutaneous endoscopic gastrostomy (PEG) placed between 1993 and 1999. Height velocity improved significantly in the group of patients with a PEG placed; however, pulmonary function declined more significantly over time. Questionnaires regarding attitude toward PEG placement were sent to patients enrolled in accredited cystic fibrosis centers in the mountain west region and to their parents. The overall response rate was 54.25% for the PEG questionnaire and 24% for the non-PEG questionnaire. Ninety-six percent of the patients with a PEG reported that weight was a problem at time of placement, and 91% reported weight gain after PEG ill placement. Sixty-four percent of the patients with a PEG reported that they would have a PEG placed if they made the decision again. Of the patients without a PEG, 60.7% thought a PEG looked bad, and 59.2% would be embarrassed to have a PEG. Forty-nine percent of patients without a PEG expressed a lack of knowledge of the pros and cons of PEG placement and 35.4% had no opinion about their knowledge of PEGs. PEG placement can be beneficial in improving nutritional status. Optimal time for PEG placement may be earlier rather than after pulmonary function has declined. People with a PEG have felt positive toward placement, and those without a PEG seem to lack knowledge about the pros and cons of PEG placement.

Approximately 10% of cystic fibrosis (CF) cases remain undiagnosed until age 18 or later and medical professionals are still unclear about the needs of these individuals. Adults with CF iii must either adapt to life with a chronic disease or transition into adulthood with CF. The purpose of this study was to address the impact of age-at-diagnosis on quality of life in a CF adult population. The psychological functioning of 21 adult CF patients (seven adult-diagnosed (AD) and 14 pediatric-diagnosed (PD)) was assessed using the Beck Depression Index (BDI)-II. A descriptive review of demographic and clinical data, which included an assessment of the financial impact of active outpatient medications, was also conducted among patients in both groups. The incidence of depression among participants was relatively low and appeared independent of age-at-diagnosis. Differences between AD and PD patients with CF in terms of demographic and clinical parameters were also minimal. (96 pages).

Aim: The aim of this thesis is to describe the process by which the inherited disease, cystic fibrosis, (CF) was recognised as an important clinical entity in the United Arab Emirates (UAE) and the Sultanate of Oman (Oman). It examines the clinical presentation of the first patients and assesses their degree of severity. Further, it describes the first studies carried out to determine the underlying CF mutations associated with the disease in the UAE and Oman. An estimate is offered of the birth frequency of the condition. Overall, the cultural, geographical and historical aspect of the societies in which the disease occurs is stressed. Methods: An initial literature search was carried out using Medline of any literature pertaining to the Arab World and CF. this was read and classified into the relevance to Arabs in general, the Middle East and then specifically the Arab (Persian) Gulf societies. Thereafter, a clinic was established at Tawam Hospital, Al Ain, UAE, for children presenting With chronic respiratory disease that could serve as a national referral centre. It was run by the Author as a service of the Paediatric Department of the UAE University Medical School. I sent a letter to every Paediatrician working in the UAE informing them of our clinic and offering our services for the diagnosis and management of chronic respiratory disease in children. This was based on the author's experience as a respiratory paediatrician in Australia and New Zealand and as the Professor of Paediatrics in the UAE. No such service then existed in the UAE. Funding was sought to establish a research programme and develop a molecular genetics laboratory in the UAE Medical School. A series of successful research applications provided the grants to commence the investigations. Once a small number of children had been identified as having CF from those referred to the respiratory clinic, the initial project was to assess and report their clinical presentation. Following this an early start was made on the identification of the mutations responsible. Once these were established an attempt was made to estimate the frequency of the condition at birth. Additional clinical studies revolved around assessing the severity of the condition that was associated with the main mutations that were identified. A clinical comparison was made with those with the mutation AF508 and the other main mutation, despite the obvious limitation of small numbers then available. Radiological assessment was made to evaluate the progression of the disease. The final aspect of the study was to assess patients from Oman and compare their findings and mutations with the neighbouring UAE. Based on information gained hypotheses are proposed regarding the spread of the gene mutation by population drift. Thesis outline: A literature review is presented in the form of a critique on the disease and a resume of the relevant aspects of the genetics of CF. Additionally, facts about the two countries' geography and history are presented. Finally, knowledge about CF mutations and population origins from other areas is presented. The second main section deals with the clinical features of the disorder as it presents in the UAE. Molecular findings are then presented and details of the common mutation found in Bedouin Arabs. Hypotheses are then presented based on the information gathered. Results: CF is not a rare disease in the Arab children of the UAE and Oman. These findings refute previous reports of CF being a rare or non-existent disease in Arabs. The condition presents with a severe clinical picture, with early colonisation of the respiratory tract with staphylococcus, haemophilus and pseudomonas organisms, even with conventional CF management practices in place. The CF mutation S549R is prevalent in Arabs of Bedouin stock, while AF508 is found in those of Baluch origin. The former may be descendants of Arabs who left southern Arabia and travelled to the Trucial Coast at the time of the destruction of the great dam at Marib. The origins of this mutation may lie in the area that corresponds to the modern Republic of Yemen. The latter groups are descendants of those who came originally from Baluchistan. It is hypothesised also that the ancestral home of the AF508 mutation may be in the geographical area now known as Baluchistan, that spans three separate modern political territories. The evidence presented supports the concept that the S549R mutation may be associated with a severe, if not the severest, clinical pattern recognised. It equates with that seen with the homozygous AF508 genotype. The absence of an additional mutation in the promoter region accounts for the different clinical pattern seen in previously described patients. Conclusions: There needs to be a major awareness of the presence of CF as a severe clinical disease in the children of the Gulf States. The clinical presentation and findings support the concept of under recognition of the disease. Climatic conditions put the children at special risk of hyponatraemia and electrolyte imbalance. The absence of surviving adults with the disease suggests premature deaths have occurred, but the high fertility rates have maintained the gene pool for this recessive disorder.

Cystic fibrosis (CF) is an inherited disease with symptoms mainly in the respiratory tract. The airway epithelium is covered with a thin layer of fluid, the airway surface liquid (ASL). The volume and composition of ASL are important in the pathogenesis of cystic fibrosis. The composition of ASL was determined. Firstly, pig airways were analyzed by X-ray microanalysis in the frozen-hydrated state. Secondly, small Sephadex beads were left to absorb the ASL in situ and were analyzed by X-ray microanalysis. The Na and Cl concentrations in the ASL of the pig were close to those of these ions in serum. Rat tracheal ASL was hypotonic. However, rat nasal fluid was hypertonic with an extremely high concentration of K. The composition of the ASL could be influenced by pharmacological stimulation. The development of transgenic mouse models for CF may help to develop therapies for the disease. The composition of mouse ASL was investigated using different collection techniques. (1) beads mounted on filter paper, (2) beads randomly spread over the airway epithelium, and (3) beads spread over the epithelium with a syringe. No significant difference could be detected between these techniques, and mouse ASL was hypotonic. Calibration curves had to be made for each element of interest. Nasal fluid from healthy human volunteers was collected with: (1) a pipette, (2) filter paper, (3) cotton wool, or (4) Sephadex beads. Collection on filter paper and equilibration with Sephadex beads gave reliable results. The Na and Cl concentrations in nasal fluid of control subjects were about the same as in serum, but the K concentration was higher. Rhinitis or primary ciliary dyskinesia patients and CF heterozygotes had abnormally high concentrations of Na and Cl in their nasal fluid (probably due to inflammation of the nasal epithelium), and CF homozygotes had even higher concentrations of Na and Cl.

Rationale: Ventilation inhomogeneity (VI) may be an early sign of obstructive airway disease. The lung clearance index (LCI) has been suggested as a sensitive marker of VI, although it has not been well characterized in young children in health and in those with CF and asthma. Objective: To determine if LCI can detect VI in asymptomatic infants and preschool-age subjects with CF or wheeze/asthma compared to healthy controls. Methods: Sulphur hexafluoride (SF6) multiple breath washout (MBW) testing was completed in all subjects. Results: LCI was found to be dependent on age in a large healthy cohort. Accounting for age, LCI was significantly elevated in disease groups compared to healthy controls in early childhood, illustrating early presence of VI in wheezy infants and the progression of disease in CF. Furthermore, the effects of breathing pattern and the variability of MBW parameters showed positive associations with age and VI.

Rationale: Ventilation inhomogeneity (VI) may be an early sign of obstructive airway disease. The lung clearance index (LCI) has been suggested as a sensitive marker of VI, although it has not been well characterized in young children in health and in those with CF and asthma. Objective: To determine if LCI can detect VI in asymptomatic infants and preschool-age subjects with CF or wheeze/asthma compared to healthy controls. Methods: Sulphur hexafluoride (SF6) multiple breath washout (MBW) testing was completed in all subjects. Results: LCI was found to be dependent on age in a large healthy cohort. Accounting for age, LCI was significantly elevated in disease groups compared to healthy controls in early childhood, illustrating early presence of VI in wheezy infants and the progression of disease in CF. Furthermore, the effects of breathing pattern and the variability of MBW parameters showed positive associations with age and VI.

Although medical advances have improved prognosis for children with cystic fibrosis (CF) and congenital heart disease (CHD), these youth experience poor psycho - social health. Embedded within the Medical Research Council’s framework, the purpose of this Dissertation was to a) examine how CF and CHD children experience physical activity, b) explore parents’ perceptions toward their child’s activity, c) develop a theory of physical activity in childhood chronic diseases, d) develop a physical activity counselling program for youth with CF and their parents, and e) evaluate the program impact on quality of life and physical activity. Study One explored how 14 CF youth experience physical activity. Active and inactive youth were characterized by different experiences, such as a sense of hope or despair. Given the burden of treatment and the fatal nature of the disease, youth negotiated temporal barriers to activity. Study Two explored perceptions toward activity among 29 CF and CHD parents. Parents discussed the benefits and barriers associated with physical activity for both child and self, and underscored the importance of role modeling. By adopting a Grounded Theory approach, the theoretical constructs from Study One and Two were crystallized to develop a theory of physical activity in youth with CF and CHD. This theory was used to develop “CF Chatters:” A Six Week Physical Activity Counselling Program for Youth with CF and their Parents, and the intervention employed behavioural self regulation ii skills. In Study Three, four case families in the CF clinic at the Hospital for Sick Children participated in CF Chatters. Improvements were noted in quality of life and physical activity, and participants described the program as convenient and relevant to their activity concerns. CF Chatters afforded therapeutic benefits to participants. By employing an eclectic qualitative approach, this Doctoral Program has made theoretical and practical contributions toward our understanding of how physical activity is experienced among children living with CF/CHD. The findings support the use of behavioural counselling as an effective and feasible modality for enhancing quality of life and physical activity. This Dissertation calls on clinicians to attend to the activity needs of chronically ill Canadian youth.

Although medical advances have improved prognosis for children with cystic fibrosis (CF) and congenital heart disease (CHD), these youth experience poor psycho - social health. Embedded within the Medical Research Council’s framework, the purpose of this Dissertation was to a) examine how CF and CHD children experience physical activity, b) explore parents’ perceptions toward their child’s activity, c) develop a theory of physical activity in childhood chronic diseases, d) develop a physical activity counselling program for youth with CF and their parents, and e) evaluate the program impact on quality of life and physical activity. Study One explored how 14 CF youth experience physical activity. Active and inactive youth were characterized by different experiences, such as a sense of hope or despair. Given the burden of treatment and the fatal nature of the disease, youth negotiated temporal barriers to activity. Study Two explored perceptions toward activity among 29 CF and CHD parents. Parents discussed the benefits and barriers associated with physical activity for both child and self, and underscored the importance of role modeling. By adopting a Grounded Theory approach, the theoretical constructs from Study One and Two were crystallized to develop a theory of physical activity in youth with CF and CHD. This theory was used to develop “CF Chatters:” A Six Week Physical Activity Counselling Program for Youth with CF and their Parents, and the intervention employed behavioural self regulation ii skills. In Study Three, four case families in the CF clinic at the Hospital for Sick Children participated in CF Chatters. Improvements were noted in quality of life and physical activity, and participants described the program as convenient and relevant to their activity concerns. CF Chatters afforded therapeutic benefits to participants. By employing an eclectic qualitative approach, this Doctoral Program has made theoretical and practical contributions toward our understanding of how physical activity is experienced among children living with CF/CHD. The findings support the use of behavioural counselling as an effective and feasible modality for enhancing quality of life and physical activity. This Dissertation calls on clinicians to attend to the activity needs of chronically ill Canadian youth.