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1.  Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganisation and absent inner dynein arms 
Human mutation  2013;34(3):462-472.
Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by cilia and sperm dysmotility. About 12% of cases show perturbed 9+2 microtubule cilia structure and inner dynein arm (IDA) loss, historically termed ‘radial spoke defect’. We sequenced CCDC39 and CCDC40 in 54 ‘radial spoke defect’ families, as these are the two genes identified so far to cause this defect. We discovered biallelic mutations in a remarkable 69% (37/54) of families, including identification of 25 (19 novel) mutant alleles (12 in CCDC39 and 13 in CCDC40). All the mutations were nonsense, splice and frameshift predicting early protein truncation, which suggests this defect is caused by ‘null’ alleles conferring complete protein loss. Most families (73%; 27/37) had homozygous mutations, including families from outbred populations. A major putative hotspot mutation was identified, CCDC40 c.248delC, as well as several other possible hotspot mutations. Together, these findings highlight the key role of CCDC39 and CCDC40 in PCD with axonemal disorganisation and IDA loss, and these genes represent major candidates for genetic testing in families affected by this ciliary phenotype. We show that radial spoke structures are largely intact in these patients and propose this ciliary ultrastructural abnormality be referred to as ‘IDA and nexin-dynein regulatory complex (N-DRC) defect’, rather than ‘radial spoke defect’.
doi:10.1002/humu.22261
PMCID: PMC3630464  PMID: 23255504
primary ciliary dyskinesia; cilia; CCDC39; CCDC40; radial spoke; dynein regulatory complex; nexin link
2.  Culture of Primary Ciliary Dyskinesia Epithelial Cells at Air-Liquid Interface Can Alter Ciliary Phenotype but Remains a Robust and Informative Diagnostic Aid 
PLoS ONE  2014;9(2):e89675.
Background
The diagnosis of primary ciliary dyskinesia (PCD) requires the analysis of ciliary function and ultrastructure. Diagnosis can be complicated by secondary effects on cilia such as damage during sampling, local inflammation or recent infection. To differentiate primary from secondary abnormalities, re-analysis of cilia following culture and re-differentiation of epithelial cells at an air-liquid interface (ALI) aids the diagnosis of PCD. However changes in ciliary beat pattern of cilia following epithelial cell culture has previously been described, which has brought the robustness of this method into question. This is the first systematic study to evaluate ALI culture as an aid to diagnosis of PCD in the light of these concerns.
Methods
We retrospectively studied changes associated with ALI-culture in 158 subjects referred for diagnostic testing at two PCD centres. Ciliated nasal epithelium (PCD n = 54; non-PCD n = 111) was analysed by high-speed digital video microscopy and transmission electron microscopy before and after culture.
Results
Ciliary function was abnormal before and after culture in all subjects with PCD; 21 PCD subjects had a combination of static and uncoordinated twitching cilia, which became completely static following culture, a further 9 demonstrated a decreased ciliary beat frequency after culture. In subjects without PCD, secondary ciliary dyskinesia was reduced.
Conclusions
The change to ciliary phenotype in PCD samples following cell culture does not affect the diagnosis, and in certain cases can assist the ability to identify PCD cilia.
doi:10.1371/journal.pone.0089675
PMCID: PMC3934921  PMID: 24586956
3.  Validation of a portable nitric oxide analyzer for screening in primary ciliary dyskinesias 
Background
Nasal nitric oxide (nNO) levels are very low in primary ciliary dyskinesia (PCD) and it is used as a screening test.
Methods
We assessed the reliability and usability of a hand-held analyser in comparison to a stationary nitric oxide (NO) analyser in 50 participants (15 healthy, 13 PCD, 22 other respiratory diseases; age 6–79 years). Nasal NO was measured using a stationary NO analyser during a breath-holding maneuver, and using a hand-held analyser during tidal breathing, sampling at 2 ml/sec or 5 ml/sec. The three methods were compared for their specificity and sensitivity as a screen for PCD, their success rate in different age groups, within subject repeatability and acceptability. Correlation between methods was assessed.
Results
Valid nNO measurements were obtained in 94% of participants using the stationary analyser, 96% using the hand-held analyser at 5 ml/sec and 76% at 2 ml/sec. The hand-held device at 5 ml/sec had excellent sensitivity and specificity as a screening test for PCD during tidal breathing (cut-off of 30 nL/min,100% sensitivity, >95% specificity). The cut-off using the stationary analyser during breath-hold was 38 nL/min (100% sensitivity, 95% specificity). The stationary and hand-held analyser (5 ml/sec) showed reasonable within-subject repeatability(% coefficient of variation = 15).
Conclusion
The hand-held NO analyser provides a promising screening tool for PCD.
doi:10.1186/1471-2466-14-18
PMCID: PMC3929562  PMID: 24507708
Nasal nitric oxide; Primary ciliary dyskinesia; Nitric oxide analyser
4.  Validation of novel wheeze phenotypes using longitudinal airway function and atopic sensitisation data in the first 6 years of life: Evidence from the Southampton Women’s Survey. 
Pediatric pulmonology  2013;48(7):683-692.
Background
In 1995 the Tucson Children’s Respiratory Study (TCRS) identified clinically distinct phenotypes amongst early wheezers; the Avon Longitudinal Study of Parents And Children (ALSPAC) has recently re-examined these.
Objectives
To validate statistically derived ALSPAC phenotypes in the Southampton Women’s Survey (SWS) using infant and 6 year lung function, and allergic sensitisation at 1, 3 and 6 years, comparing these with TCRS phenotypes.
Methods
Complete 6 year follow-up data were available for 926 children, selected from 1973 infants born to 12,579 women characterised pre-conception. 95 children had V’maxFRC and FEV0.4 measured age 5-14 weeks using rapid compression/raised volume techniques. At 6 years we performed spirometry (n=791), fractional exhaled nitric oxide (FeNO, n=589) and methacholine challenge (n=234). Skin prick testing was performed at 12m, 3 and 6 years (n=1494, 1255, 699, respectively). Using wheeze status questionnaire data at 6m, 12m, 2, 3 and 6 years we classified children into TCRS (never, transient early, persistent, late-onset) and ALSPAC based groups (never, early, transient, intermediate-onset, late-onset, persistent).
Results
Amongst ALSPAC groups, persistent and late-onset wheeze were associated with atopy at 3 and 6 years, whilst intermediate-onset wheeze showed earlier atopic association at 1 year; all three were associated with FeNO at 6 years. Persistent wheezers had lower infant (V’maxFRC p<0.05) and 6 year lung function (FEV1, FEV1/FVC and FEF25-75, p<0.05), whilst late and intermediate-onset wheezers showed no lung function deficits. Transient wheezers were non-atopic but showed persistent lung function deficits (V’maxFRC in infancy, FEV1 and FEF25-75 at 6 years, all p<0.05). Those who wheezed only in the first year (early phenotype) showed no lung function deficits. No associations were seen with 6 years bronchial hyper-responsiveness or infancy FEV0.4.
Conclusion
SWS cohort data validates the statistically derived ALSPAC 6-class model. In particular, lung function and atopy successfully differentiate persistent, late-onset and intermediate-onset wheeze, whilst the Tucson ‘transient early’ wheeze phenotype can be sub-classified into groups that reflect early lung function. Since the 4-class model fails to adequately differentiate phenotypes based on lung function and atopy, we propose that strong consideration be given to using the 6-class paradigm for longitudinal outcome work in wheezing with onset in early life.
doi:10.1002/ppul.22766
PMCID: PMC3689612  PMID: 23401430
Wheeze; asthma; phenotype; lung function; cohort; atopy
5.  THE RELATIONSHIP BETWEEN MATERNAL ADIPOSITY AND INFANT WEIGHT GAIN AND CHILDHOOD WHEEZE AND ATOPY 
Thorax  2013;68(4):372-379.
Background
Obesity and asthma have increased in westernised countries. Maternal obesity may increase childhood asthma risk. If this relation is causal it may be mediated through factors associated with maternal adiposity, such as fetal development, pregnancy complications or infant adiposity. We investigated the relationships of maternal BMI and fat mass with childhood wheeze and examined the influences of infant weight gain and childhood obesity.
Methods
Maternal pre-pregnancy BMI and estimated fat mass (from skinfold thicknesses) were related to asthma, wheeze and atopy in 940 children. Transient or persistent/late wheeze was classified using questionnaire data collected at ages 6, 12, 24 and 36 months and 6 years. At 6 years, skin prick testing was conducted and exhaled nitric oxide and spirometry measured. Infant adiposity gain was calculated from skinfold thickness at birth and 6 months.
Results
Greater maternal BMI and fat mass were associated with increased childhood wheeze (RR 1.08 per 5 kg m−2, p=0.006; RR 1.09 per 10 kg, p=0.003); these reflected associations with transient wheeze (RR 1.11, p=0.003; RR 1.13, p=0.002, respectively) but not with persistent wheeze or asthma. Infant adiposity gain was associated with persistent wheeze but not significantly. Adjusting for infant adiposity gain or BMI at 3 or 6 years did not reduce the association between maternal adiposity and transient wheeze. Maternal adiposity was not associated with offspring atopy, exhaled nitric oxide, or spirometry.
Discussion
Greater maternal adiposity is associated with transient wheeze but not asthma or atopy, suggesting effects upon airway structure/function but not allergic predisposition.
doi:10.1136/thoraxjnl-2012-202556
PMCID: PMC3661999  PMID: 23291350
adiposity; body mass index; obesity; asthma; allergic sensitisation
7.  Patterns of fetal and infant growth are related to atopy and wheezing disorders at age 3 years 
Thorax  2010;65(12):1099-1106.
Background
Little is known about whether patterns of growth are associated with altered respiratory and immune development. This study relates prenatal and infant growth patterns to wheeze and atopy at age 3 years
Methods
Birth weight and length were measured in 1548 children born at term. Conditional fetal head and abdominal circumference growth velocities were calculated from antenatal ultrasound measurements. Conditional postnatal growth velocities were calculated from infant weight, length and adiposity data. .Measures of size and conditional growth were related to parentally-reported infant and early childhood wheeze and to atopic status at age 3.
Results
Atopy risk increased by 46% per standard deviation (SD) increase in abdominal circumference growth velocity from 11-19 weeks’ gestation but by 20% per SD decrease in abdominal growth velocity from 19-34 weeks (p=0.007 and p=0.011). Atopic wheeze risk increased by 20% per SD decrease in 19-34 week abdominal growth (p=0.046). Non-atopic wheeze risk increased by 10% per SD decrease in 11-19 week head circumference growth. Greater relative infant weight and adiposity gains were associated with both atopic and non-atopic wheeze.
Conclusions
Rapid growth during 11-19 weeks’ gestation followed by growth faltering is associated with atopy, suggesting that influences affecting fetal growth may also alter immune development. A lower early fetal growth trajectory is associated with non-atopic wheeze, possibly reflecting an association with smaller airways. An association between postnatal adiposity gain and wheeze may partly reflect prenatal influences that cause fetal growth to falter but are then followed by postnatal adiposity gain.
doi:10.1136/thx.2010.134742
PMCID: PMC3685135  PMID: 20956394
asthma; preschool-wheeze; allergic sensitisation; growth; nutrition
8.  Maternal late-pregnancy serum 25-hydroxyvitamin D in relation to childhood wheeze and atopic outcomes 
Thorax  2012;67(11):950-956.
Background
Studies exploring the relationship between prenatal vitamin D exposure and childhood asthma have yielded conflicting results. Higher vitamin D intake during pregnancy has been shown to lower the risk of childhood wheeze, yet a study of maternal late-pregnancy serum 25-hydroxyvitamin D suggested higher serum concentrations may be associated with increased childhood asthma.
Objective
To assess the relationship between mothers’ serum 25-hydroxyvitamin D status and asthma and wheeze phenotypes in their children at age 6 years. Secondly, to explore the relationship between maternal 25-hydroxyvitamin D status and objective measures of childhood atopy and lung function.
Methods
Serum 25-hydroxyvitamin D was measured at 34 weeks’ gestation in the mothers of 860 children born at term. Wheeze was classified as either transient or persistent/late using questionnaire data collated from 6, 12, 24 and 36 months and 6 years. At 6 years spirometry was performed and atopic status was determined by skin prick testing, exhaled nitric oxide was measured in 451 and bronchial hyperresponsiveness in 216 children.
Results
There were no significant associations between maternal late-pregnancy 25-hydroxyvitamin D status and either asthma or wheeze at age 6 years. Maternal vitamin D status was not associated with transient or persistent/late wheeze; no significant association was found between persistent/late wheeze when subdivided according to atopic status. No associations were found with skin sensitisation or lung function.
Conclusions
This study provides no evidence that exposure to higher concentrations of 25-hydroxyvitamin D in maternal serum during late pregnancy increases the risk of childhood asthma, wheeze or atopy.
doi:10.1136/thoraxjnl-2012-201888
PMCID: PMC3679514  PMID: 22707522
asthma epidemiology; asthma; paediatric asthma
9.  Beyond Labelling: What Strategies Do Nut Allergic Individuals Employ to Make Food Choices? A Qualitative Study 
PLoS ONE  2013;8(1):e55293.
Objective
Food labelling is an important tool that assists people with peanut and tree nut allergies to avoid allergens. Nonetheless, other strategies are also developed and used in food choice decision making. In this paper, we examined the strategies that nut allergic individuals deploy to make safe food choices in addition to a reliance on food labelling.
Methods
Three qualitative methods: an accompanied shop, in-depth semi-structured interviews, and the product choice reasoning task – were used with 32 patients that had a clinical history of reactions to peanuts and/or tree nuts consistent with IgE-mediated food allergy. Thematic analysis was applied to the transcribed data.
Results
Three main strategies were identified that informed the risk assessments and food choice practices of nut allergic individuals. These pertained to: (1) qualities of product such as the product category or the country of origin, (2) past experience of consuming a food product, and (3) sensory appreciation of risk. Risk reasoning and risk management behaviours were often contingent on the context and other physiological and socio-psychological needs which often competed with risk considerations.
Conclusions
Understanding and taking into account the complexity of strategies and the influences of contextual factors will allow healthcare practitioners, allergy nutritionists, and caregivers to advise and educate patients more effectively in choosing foods safely. Governmental bodies and policy makers could also benefit from an understanding of these food choice strategies when risk management policies are designed and developed.
doi:10.1371/journal.pone.0055293
PMCID: PMC3558473  PMID: 23383141
10.  Maternal Plasma Phosphatidylcholine Fatty Acids and Atopy and Wheeze in the Offspring at Age of 6 Years 
Variation in exposure to polyunsaturated fatty acids (PUFAs) might influence the development of atopy, asthma, and wheeze. This study aimed to determine whether differences in PUFA concentrations in maternal plasma phosphatidylcholine are associated with the risk of childhood wheeze or atopy. For 865 term-born children, we measured phosphatidylcholine fatty acid composition in maternal plasma collected at 34 weeks' gestation. Wheezing was classified using questionnaires at 6, 12, 24, and 36 months and 6 years. At age of 6 years, the children underwent skin prick testing, fractional exhaled nitric oxide (FENO) measurement, and spirometry. Maternal n-6 fatty acids and the ratio of n-3 to n-6 fatty acids were not associated with childhood wheeze. However, higher maternal eicosapentaenoic acid, docosahexaenoic acid, and total n-3 fatty acids were associated with reduced risk of non-atopic persistent/late wheeze (RR 0.57, 0.67 and 0.69, resp. P = 0.01, 0.015, and 0.021, resp.). Maternal arachidonic acid was positively associated with FENO (P = 0.024). A higher ratio of linoleic acid to its unsaturated metabolic products was associated with reduced risk of skin sensitisation (RR 0.82, P = 0.013). These associations provide some support for the hypothesis that variation in exposure to n-6 and n-3 fatty acids during pregnancy influences the risk of childhood wheeze and atopy.
doi:10.1155/2012/474613
PMCID: PMC3463812  PMID: 23049600
11.  The strategies that peanut and nut-allergic consumers employ to remain safe when travelling abroad 
Background
An understanding of the management strategies used by food allergic individuals is needed as a prerequisite to improving avoidance and enhancing quality of life. Travel abroad is a high risk time for severe and fatal food allergic reactions, but there is paucity of research concerning foreign travel. This study is the first to investigate the experiences of, and strategies used by peanut and tree nut allergic individuals when travelling abroad.
Methods
Thirty-two adults with a clinical history of reaction to peanuts or tree nuts consistent with IgE-mediated allergy participated in a qualitative interview study.
Results
Travel abroad was considered difficult with inherent risks for allergic individuals. Many participants recounted difficulties with airlines or restaurants. Inconsistency in managing allergen avoidance by airlines was a particular risk and a cause of frustration to participants. Individuals used a variety of strategies to remain safe including visiting familiar environments, limiting their activities, carrying allergy information cards in the host language, preparing their own food and staying close to medical facilities.
Conclusions
Participants used a variety of allergen avoidance strategies, which were mostly extensions or modifications of the strategies that they use when eating at home or eating-out in the UK. The extended strategies reflected their recognition of enhanced risk during travel abroad. Their risk assessments and actions were generally well informed and appropriate. A need for airline policy regarding allergy to be declared and adhered to is needed, as is more research to quantify the true risks of airborne allergens in the cabin. Recommendations arising from our study are presented.
doi:10.1186/2045-7022-2-12
PMCID: PMC3480958  PMID: 22776751
Food allergy; Peanut allergy; Tree nut allergy; Holiday; Travel; Airline
12.  What factors affect the carriage of epinephrine auto-injectors by teenagers? 
Background
Teenagers with allergies are at particular risk of severe and fatal reactions, but epinephrine auto-injectors are not always carried as prescribed. We investigated barriers to carriage.
Methods
Patients aged 12-18 years old under a specialist allergy clinic, who had previously been prescribed an auto-injector were invited to participate. Semi-structured interviews explored the factors that positively or negatively impacted on carriage.
Results
Twenty teenagers with food or venom allergies were interviewed. Only two patients had used their auto-injector in the community, although several had been treated for severe reactions in hospital. Most teenagers made complex risk assessments to determine whether to carry the auto-injector. Most but not all decisions were rational and were at least partially informed by knowledge. Factors affecting carriage included location, who else would be present, the attitudes of others and physical features of the auto-injector. Teenagers made frequent risk assessments when deciding whether to carry their auto-injectors, and generally wanted to remain safe. Their decisions were complex, multi-faceted and highly individualised.
Conclusions
Rather than aiming for 100% carriage of auto-injectors, which remains an ambitious ideal, personalised education packages should aim to empower teenagers to make and act upon informed risk assessments.
doi:10.1186/2045-7022-2-3
PMCID: PMC3299626  PMID: 22409884
Food allergy; adolescent; adherence; anaphylaxis; auto-injector; patient education
13.  Using 'may contain' labelling to inform food choice: a qualitative study of nut allergic consumers 
BMC Public Health  2011;11:734.
Background
Precautionary 'may contain' warnings are used to indicate possible allergen contamination. Neither food safety nor foods labelling legislation address this issue. The aim of this study is to understand how peanut and nut allergic adults interpret 'may contain' labelling and how they use this information when purchasing food.
Methods
Qualitative methods were used to explore both behaviour and attitudes. The behaviour and 'thinking aloud' of 32 participants were recorded during their normal food shop. A semi-structured interview also explored participants' views about 13 potentially problematic packaged foods. Transcribed data from these tasks were analysed to explore the interpretation of 'may contain' labelling and how this influenced food choice decisions.
Results
Peanut and nut allergic individuals adopt a complex range of responses and strategies to interpret 'may contain' labelling. Many claimed such labelling was not credible or desirable; many ignored it whilst some found it helpful and avoided products with all such labelling. Interpretation and consequent decisions were not only based on the detail of the labelling but also on external factors such as the nature of the product, the perceived trustworthiness of the producer and on the previous experience of the nut allergic individual.
Conclusions
'May contain' labelling was interpreted in the light of judgements about the product, producer and previous personal experience. It is vital that these interpretation strategies are taken into account by those responsible for labelling itself and for the provision of advice to nut allergic individuals. Suggestions to improve labelling and advice to the allergic individual are considered.
doi:10.1186/1471-2458-11-734
PMCID: PMC3195759  PMID: 21943285
14.  Primary ciliary dyskinesia: current state of the art 
Archives of Disease in Childhood  2007;92(12):1136-1140.
Primary ciliary dyskinesia (PCD) is usually inherited as an autosomal recessive disorder and presents with upper and lower respiratory tract infection, and mirror image arrangement in around 50% of cases. Cilia dysfunction is also implicated in a wider spectrum of disease, including polycystic liver and kidney disease, central nervous system problems including retinopathy and hydrocephalus, and biliary atresia. Cilia are complex structures, containing more than 250 proteins; recent studies have begun to locate PCD genes scattered throughout the genome. Screening tests for PCD include nasal nitric oxide and in vivo tests of ciliary motility such as the saccharin test. Specific diagnosis requires examination of cilia by light and electron microscopy, with epithelial culture in doubtful cases. This is only available in supra‐regional centres, recently centrally funded by the National Commissioning Group. Treatment is not evidence based and recommendations are largely extrapolated from cystic fibrosis and other suppurative lung diseases.
doi:10.1136/adc.2006.096958
PMCID: PMC2066071  PMID: 17634184
15.  Diagnosing primary ciliary dyskinesia 
Thorax  2007;62(8):656-657.
A nationally funded diagnostic service should lead to improved outcome
doi:10.1136/thx.2007.083147
PMCID: PMC2117265  PMID: 17687094

Results 1-15 (15)