Maternal vitamin D and E intakes during pregnancy are associated with asthma in children.

Are maternal vitamin D and E intakes during pregnancy associated with asthma in 10-year-old children? In a longitudinal study of 1924 children born to women recruited during pregnancy, maternal vitamin D intake during pregnancy was assessed by the Food Frequency Questionnaire (FFQ) and vitamin E by FFQ and plasma α-tocopherol; respiratory questionnaires were completed for the 10-year-old children. Their treatment for asthma was also ascertained using administrative data. Longitudinal analyses included data collected at 1, 2, 5 and 10 years. Symptom data were available for 934 (49%) children and use of asthma medication for 1748 (91%). In the children maternal vitamin D intake during pregnancy was negatively associated with doctor-diagnosed asthma at 10 years of age (OR per intake quintile 0.86, 95% CI 0.74-0.99) and over the first 10 years (hazard ratio 0.90, 95% CI 0.81-1.00). Maternal plasma α-tocopherol at 11 weeks gestation was negatively associated with children receiving asthma treatment (OR per standard deviation increase 0.52, 95% CI 0.31-0.87). Maternal vitamin E intake was negatively associated with doctor-diagnosed asthma (OR 0.89, 95% CI 0.81-0.99) in the first 10 years. Low maternal vitamin D and E intakes during pregnancy are associated with increased risk of children developing asthma in the first 10 years of life. These associations may have significant public health implications.

Pharmacovigilance in children: detecting adverse drug reactions in routine electronic healthcare records. A systematic review.

AIMS: A systematic review of the literature published in English over 10 years was undertaken in order to describe the use of electronic healthcare data in the identification of potential adverse drug reactions (ADRs) in children. METHODS: MEDLINE and EMBASE were searched using MESH headings and text words. Titles, keywords and abstracts were checked for age <18 years, potential ADRs and electronic healthcare data. Information extracted included age, data source, pharmacovigilance method, medicines and ADRs. Studies were quality assessed. RESULTS: From 14 804 titles, 314 had a full text review and 71 were included in the final review. Fifty were published in North America, 10 in Scandinavia. Study size ranged from less than 1000 children to more than 10 million. Sixty per cent of studies used data from one source. Comparative observational studies were most commonly reported (66.2%) with 15% using passive surveillance. Electronic healthcare data set linkage and the quality of the data source were poorly reported. ADRs were classified using the International Classification of Disease (ICD10). Multi-system reactions were most commonly studied, followed by central nervous system and mental and behavioural disorders. Vaccines were most frequently prescribed followed by corticosteroids, general anaesthetics and antidepressants. CONCLUSIONS: Routine electronic healthcare records were increasingly reported to be used for pharmacovigilance in children. This growing and important health protection activity could be enhanced by consistent reporting of studies to improve the identification, interpretation and generalizability of the evidence base.

'The more you link, the more you risk ' - a focus group study exploring views about data linkage for pharmacovigilance.

AIMS: The aim of this study was to assess opinions of frontline healthcare professionals on the linking of routinely collected national (Scottish) paediatric data for the purpose of identifying earlier signals of adverse drug reactions. METHODS: Stratified purposive sampling led to profession-specific focus groups with pharmacists, nurses and medical doctors from primary and secondary care in different Scottish Health Boards. A topic guide was used to explore the proposed data linkage of routinely collected paediatric data. Discussions were audio recorded and transcribed verbatim. Transcripts were analysed using a framework approach to identify themes. Ethical approval was obtained from the North of Scotland Research Ethics Service. RESULTS: Six focus groups were conducted in 2011 with 22 participants. Views of the proposed data linkage were generally positive. Several issues were identified, including lack of clarity on data ownership and concerns about diversion of funding. Identified issues were at a practical rather than a strategic level. CONCLUSIONS: This study identified that professional stakeholder groups are likely to find linkage of paediatric patient data acceptable. Barriers identified could be addressed. Focus group participants commented on the importance of informing patients and members of the public about the benefits of linking healthcare data. These findings clarify the steps that should be taken to ensure the acceptability of data linkage for pharmacovigilance.

Development of an enantiomer selective microsampling assay for the quantification of ketorolac suitable for paediatric pharmacokinetic studies.

BACKGROUND: Ketorolac, a potent nonsteroidal anti-inflammatory drug used for pain control in children, exists as a racemate of inactive R (+) and active S (-) enantiomers. AIM: To develop a microsampling assay for the enantioselective analysis of ketorolac in children. METHODS: Ketorolac enantiomers were extracted from 50 µl of plasma by liquid­liquid extraction and separated on a ChiralPak AD-RH. Detection was by a TSQ quantum triple quadrupole mass spectrometer with an electrospray ionisation source operating in a positive ion mode. Five children (age 13.8 (1.6) years, weight 52.7 (7.2) kg), were administered intravenous ketorolac 0.5mg/kg (maximum 10mg) and blood samples were taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h post administration. CL, VD and t1/2 were calculated based on non-compartmental methods. RESULTS: The standard curves for R (+) and S (-) ketorolac were linear in the range 0­2000 ng/ml. The LLOQs of the method were 0.15 ng on column and 0.31 ng on column for R (+) and S (-) ketorolac, respectively. The median (range) VD and CL of R (+) and S (-) ketorolac were 0.12 l/kg (0.07­0.17), 0.017 l/h/kg (0.12­0.29) and 0.17 (0.09­0.31) l/kg, 0.049 (0.02­0.1) l/h/kg, p = 0.043), respectively. The median (range) elimination half-life (t1/2) of the R (+) and S (-) ketorolac was 5.0 h (2.5­5.8) and 3.1 h (1.8­4.4), p = 0.043), respectively. CONCLUSION: The development of a simple, rapid and reliable ketorolac assay suitable for paediatric PK studies is reported.

CMIP and ATP2C2 modulate phonological short-term memory in language impairment.

Specific language impairment (SLI) is a common developmental disorder characterized by difficulties in language acquisition despite otherwise normal development and in the absence of any obvious explanatory factors. We performed a high-density screen of SLI1, a region of chromosome 16q that shows highly significant and consistent linkage to nonword repetition, a measure of phonological short-term memory that is commonly impaired in SLI. Using two independent language-impaired samples, one family-based (211 families) and another selected from a population cohort on the basis of extreme language measures (490 cases), we detected association to two genes in the SLI1 region: that encoding c-maf-inducing protein (CMIP, minP = 5.5 x 10(-7) at rs6564903) and that encoding calcium-transporting ATPase, type2C, member2 (ATP2C2, minP = 2.0 x 10(-5) at rs11860694). Regression modeling indicated that each of these loci exerts an independent effect upon nonword repetition ability. Despite the consistent findings in language-impaired samples, investigation in a large unselected cohort (n = 3612) did not detect association. We therefore propose that variants in CMIP and ATP2C2 act to modulate phonological short-term memory primarily in the context of language impairment. As such, this investigation supports the hypothesis that some causes of language impairment are distinct from factors that influence normal language variation. This work therefore implicates CMIP and ATP2C2 in the etiology of SLI and provides molecular evidence for the importance of phonological short-term memory in language acquisition.

Alpha-nicotinic acetylcholine receptor and tobacco smoke exposure: effects on bronchial hyperresponsiveness in children.

BACKGROUND: The CHRNA 3 and 5 genes on chromosome 15 encode the alpha subunits of the nicotinic acetylcholine receptor, mediating airway cholinergic activity. Polymorphisms are associated with cigarette smoking, chronic obstructive pulmonary disease, and lung cancer. AIMS: To determine possible associations between CHRNA 3/5 SNP rs8034191 and asthma or lung function in children in one local and one replicate multinational population, and assess if tobacco smoke modified the associations. MATERIALS AND METHODS: The rs8034191 SNP genotyped in 551 children from the environment and childhood asthma (ECA) birth cohort study in Oslo, Norway, and in 516 families from six European centers [the Genetics of Asthma International Network (GAIN) study] was tested for genotypic or allelic associations to current or history of asthma, allergic sensitization (≥ one positive skin prick tests), bronchial hyperresponsiveness (BHR), and lung function (FEV(1%) of predicted and FEV(1) /FVC ratio over/ below the 5th percentile). RESULTS: Although the TT and CT genotypes at SNP rs 8034191 were overall significantly associated with BHR (OR = 3.9, 95% CI 1.5-10.0, p = 0.005), stratified analyses according to exposure to maternal smoking in-utero or indoor smoking at 10 yrs of age showed significant association (OR = 4.4, 95% CI 1.5-12.6, p = 0.006 and OR 5.6, 95% CI 1.7-18.5, p = 0.004, respectively) only in the non-exposed and not in exposed children. The SNP-BHR association was replicated in the non-tobacco-smoke-exposed subjects in one of the GAIN centers (BHR associated with the T allele (p = 0.034)), but not in the collated GAIN populations. Asthma, allergic sensitization, and lung function were not associated with the rs8034191 alleles. CONCLUSION: An interaction between tobacco smoke exposure and a CHRNA3/5 polymorphism was found for BHR in children, but CHRNA3/5 was not associated with asthma or lung function.

First- and second-trimester fetal size and asthma outcomes at age 10 years.

RATIONALE: Greater early fetal size is associated with reduced asthma risk and improved lung function in early childhood. OBJECTIVES: To test the hypothesis that associations between early fetal size, asthma symptoms, and lung function persist into later childhood. METHODS: In a longitudinal study, first- and second-trimester fetal measurements were recorded. At 10 years of age a respiratory questionnaire was completed. Spirometry, bronchial challenge, and skin-prick testing were undertaken in a subset. MEASUREMENTS AND MAIN RESULTS: Fetal measurements were available in the first trimester for 853 individuals and the second trimester for 1,453. Questionnaires were returned for 927 children and 449 underwent detailed phenotyping. For each millimeter increase in first trimester size, asthma risk reduced by 6% (95% confidence interval[CI], 1­11) and FEV1 was higher by an average of 6 ml (95% CI, 1­11).First-trimester size was reduced in those with asthma at both 5 and 10 years compared with early or late onset wheeze (P , 0.02). Compared with persistent high growth in first and second trimesters,persistent low growth was associated with increased asthma risk(odds ratio, 2.8; 95% CI, 1.2­6.9) and a mean reduction in FEV1 of 103 ml (95% CI, 13­194), whereas increasing fetal size was associated with increased eczema risk (odds ratio, 2.5; 95% CI, 1.2­5.3). CONCLUSIONS: Reduced fetal size from the first trimester is associated with increased risk for asthma and obstructed lung function in childhood. Relative change in size after the first trimester is associated with eczema.

Paracetamol prescribing in primary care: too little and too much?

AIMS: To assess the level of paracetamol off label prescribing in the community and the potential for paracetamol under or overdosing. METHODS: The Scottish Practice Team Information (PTI) database containing prescribing data for approximately 35,839 children aged (0-12 years) was analysed for paracetamol prescriptions for the year 2006. Off label prescribing was defined as prescribing outside the BNFc age and dose recommendations. RESULTS: Two thousand seven hundred and sixty-one children aged 0-12 years were issued with 4423 prescriptions for paracetamol. (1446 males). Children 1-5 years (1329, 42.2%) accounted for 48.9% (2164) of all paracetamol prescriptions. Eighteen per cent (793) of individual prescriptions were off label and after accounting for repeat prescriptions 625 (22.75%) individuals were exposed to off label prescriptions. A further 15% (668) of prescriptions contained insufficient dosage data to determine their status, 13.3% (368) being underdosed and 4.4% (121) overdosed at least once during the study year. In total 11.3% (502) of all prescriptions were classified as underdose, 2.9% (127) as overdose and 15% (667) had no dosage instructions. Age was significantly related to non recommended dosage (χ(2) test, P < 0.001). Children 1-3 months old were at highest risk of being overdosed; 27% of prescriptions recommended actual or potential overdosage and 25% (354) of children aged 6-12 years were prescribed an actual or potential underdose. Overall 57.2% of all prescriptions failed to comply with current BNFc recommendations. CONCLUSION: Paracetamol off label prescribing is common in primary care, with relatively high levels of potential overdosing in the youngest children and potential underdosing in the oldest children.

Using primary care prescribing databases for pharmacovigilance.

AIMS: In the UK, adverse drug reactions (ADRs) are responsible for over 6.5% of all hospital admissions, representing a significant morbidity and cost burden to the health service. We aimed to develop an ADR monitoring system capable of identifying the reasons for patient discontinuation of drug therapy within 6 months of the index prescription. METHODS: Patients first prescribed amlodipine between 1 March 2004 and 28 February 2007 who discontinued their amlodipine medication within 6 months of the index prescription were identified from the practice team information (PTI) database. Once identified, reasons for amlodipine discontinuation were assessed by an electronic database search using relevant Readcodes and key words and by a direct approach to the primary care medical records. RESULTS: The PTI database identified 995 patients [61.4% females, mean age 65.9 years (SD 12.4 years)] who discontinued amlodipine within 6 months of an index prescription. An electronic search of the database, using Readcodes, identified that 19.4% (193) of patients who discontinued their medication had an ADR recorded in the database. Six (20%) of 30 participating primary care practices, contributing to the PTI database, agreed to be approached directly and supply the reasons for discontinuation for the 51 patients identified as having discontinued amlodipine in their practices. Completed data were returned for all 51 patients, 98% of whom discontinued amlodipine due to an ADR or adverse drug event. CONCLUSIONS: The results of this study confirm that primary care prescribing databases can be easily used to identify the frequency and nature of ADRs occurring in an ADR-enriched population identified through medication discontinuation.

First trimester maternal tobacco smoking habits and fetal growth.

RATIONALE: Maternal smoking in pregnancy is associated with reduced birth weight and childhood lung function. This study determined when maternal smoking first influences fetal growth and how this relates to childhood respiratory outcomes. METHODS: A longitudinal cohort of 1924 pregnant women was recruited. Fetal ultrasound measurements at 11 weeks (crown-rump length, CRL) and at 20 weeks gestation (femur length, FL, and biparietal diameter, BPD) and birth measurements were recorded. Childhood respiratory symptoms and spirometry were ascertained. RESULTS: Of the 1924 original study participants, fetal size was determined in 903 in the first trimester, 1544 in the second trimester and at term in 1737 infants. Maternal smoking when first pregnant was reported in 593 (31%) and was not associated with reduced CRL. There was an inverse exposure-response relationship between cigarette consumption and FL (mean reduction in lowest compared with highest tertile 0.91 cm, p=0.033). Birth weight and length of those born to mothers who did (n=331) and did not (n=56) reduce cigarette consumption were similar and reduced compared with 186 infants whose mothers quit during the first trimester (p < or = 0.020). Children of mothers who continued smoking had increased wheeze at age 2 years (OR 1.58, p=0.017) and GP visits with wheeze at age 5 years (OR 2.18, p=0.030) and mean reduction in forced expiratory volume in 1 s of 62 ml (p=0.014) compared with controls. CONCLUSIONS: Maternal smoking is associated with reduced fetal measurements in the second and third trimesters but not in the first trimester. Mothers who do not quit smoking during the first trimester deliver smaller infants who go on to have adverse respiratory outcomes in childhood.

Associations between fetal size, maternal {alpha}-tocopherol and childhood asthma.

BACKGROUND The origins of respiratory disease might be traced back to exposures during fetal life. The aim of the present study was to explore whether there was a relationship between fetal size and respiratory outcomes at 5 years of age in the context of fetal exposure to vitamin E. METHODS A longitudinal birth cohort study was recruited (n=1924). Antenatal ultrasound scan results were identified and the following recorded: crown-rump length (CRL) in the first trimester; femur length (FL) and biparietal diameter (BPD) in the second trimester. Maternal plasma alpha-tocopherol (vitamin E) was measured at the time of the first trimester scan. At 5 years, wheeze and asthma symptoms were reported by questionnaire, and spirometry was measured. RESULTS CRL, spirometry and questionnaire data at 5 years were available for 835, 579 and 1145 individuals, respectively. There were positive associations between CRL and forced expiratory volume in 1 s (FEV(1); 5 ml increase in FEV(1) per mm CRL, p=0.001, n=283), forced vital capacity (FVC; 6 ml increase in FVC per mm CRL, p=0.001) and forced expiratory flow between 25% and 75% of FVC (FEF(25-75); 0.008 ml/s increase in FEF(25-75) per mm CRL, p=0.023), and inverse relationships with CRL and current wheeze (OR 0.59 per CRL quartile, p=0.026, n=547) and asthma (OR 0.55 per CRL quartile p=0.011). CRL was positively associated with maternal plasma alpha-tocopherol (p=0.002). CONCLUSIONS These findings support the concept of very early fetal programming of respiratory disease. Maternal vitamin E status may be one determinant for growth of the fetus and fetal lungs during early pregnancy.

Can finger-prick sampling replace venous sampling to determine the pharmacokinetic profile of oral paracetamol?

UNLABELLED: WHAT IS ALREADY KNOWN ABOUT THE SUBJECT: Finger-prick blood samples are increasingly used for the clinical and biomedical measurement of drugs and endogenous substance concentration. The use of different sampling sites can give rise to different drug concentration measurements. WHAT THIS STUDY ADDS: During the absorption phase, the paracetamol concentration in finger-prick blood samples is significantly greater than that in venous blood samples, following oral administration. Finger-prick and venous blood samples will result in equivalent pharmacokinetic parameters of oral paracetamol only after distribution equilibrium is attained. The drive to increase the availability of paediatric pharmacokinetic data with minimum blood loss has led to the development of micro-sampling techniques. However studies have suggested that pharmacokinetic data from venous or capillary blood samples may not be directly comparable. AIM: The aim of this study was to determine whether paracetamol demonstrates concentration differences between finger-prick and venous blood samples. METHODS: Paired finger-prick and venous blood samples were taken at 0, 15, 30 and 60 min following 1 g oral paracetamol, from 12 male adult subjects. Paracetamol concentration was determined using HPLC and UV detection with a LLOQ of 2200 pg on column. Intra-assay coefficient of variation for paracetamol at the LLOQ was 3%. RESULTS: At 15, 30, and 60 min post dose the median finger-prick paracetamol concentration was 349%, 72%, and 9.3% greater than the equivalent venous concentrations, respectively. Regression analysis confirmed a significant relationship between finger-prick and venous paracetamol concentrations at 15 min (r(2) = 0.81, P = 0.006), at 30 min (r(2) = 0.82, P < 0.0001) and at 60 min (r(2) = 0.87, P < 0.0001) post dose. The regression equation for venous and finger-prick blood concentrations at 15, 30 and 60 min post dose were Venous(15) = Finger(15) - 3.4, Venous(30) = Finger(30) - 3.4 and Venous(60) = 0.68 Finger(60) + 3.06, respectively. CONCLUSIONS: Paracetamol demonstrates an arteriovenous difference in concentration, and the use of finger-prick samples may give rise to results which differ from those obtained with traditional venous sampling especially during the first 1 h following drug ingestion.

A pilot study to evaluate a community pharmacy-based monitoring system to identify adverse drug reactions associated with paediatric medicines use.

INTRODUCTION: Current pharmacovigilance systems are limited by spontaneous reporting of adverse drug reactions (ADRs), lack of a denominator, and lower than expected reporting rates. The aim of our study was to undertake a formal pilot evaluation of a community pharmacy-led ADR monitoring system. METHODS: The setting was community pharmacies in five Health Boards areas of Scotland. Subjects were parents, guardians, or children presenting prescriptions for children 16 years and under prescribed serotonin specific reuptake inhibitors (SSRI), anticonvulsants, or medicines for the treatment of attention deficit hyperactivity disorder (ADHD). All pharmacies (n = 827) were invited to participate. Over a 3-month period they were asked to identify prescriptions for targeted medicines and give out an ADR questionnaire. Questionnaire content included child demography, duration of medicine use, indication, perceived ADRs, and their description and severity. The study was approved by the North of Scotland Research Ethics Committee. RESULTS: Seventy-two community pharmacists (8.7%) agreed to take part. Two hundred and twenty-nine questionnaires were distributed and 55 (24%) completed and returned by parents. Forty-one questionnaires related to ADHD medications, 13 to anticonvulsants, and 1 to an SSRI. Thirty questionnaires reported 44 possible ADRs, 19 of which were related to methylphenidate. CONCLUSIONS: The proposed ADR monitoring system identified expected ADRs thus demonstrating face and content validity for our approach. However the process was limited by low community pharmacist participation rates and low questionnaire return rates.

Views of parents and pharmacists following participation in a paediatric pharmacovigilance study.

OBJECTIVE: To explore the experiences and views of community pharmacists and parents participating in a prospective paediatric pharmacovigilance study. METHOD: Twenty-five pharmacists and 32 parents were approached for telephone interview. Interviews were audio-recorded, transcribed and analysed thematically to identify recurring issues and themes. RESULTS: Seventeen pharmacists and 22 parents were interviewed. Parents and pharmacists agreed that more information about the side effects of medicines in children was required. Both groups reported willingness to participate in future prospective pharmacovigilance studies, although pharmacists expressed concerns about the lack of financial incentives. Pharmacists reported that parents had concerns regarding the confidentiality of their child's ADR data and the study data collection process. CONCLUSION: This study highlighted positive and negative opinions of parents and pharmacists regarding their experiences in this research project. Maintaining confidentiality in relation to indication and medicines prescribed were important issues for parents whereas time constraints and lack of financial incentives were key issues influencing participation by community pharmacists.

Early identification of atopy in the prediction of persistent asthma in children.

The long-term solution to the asthma epidemic is thought to be prevention, and not treatment of established disease. Atopic asthma arises from gene-environment interactions, which mainly take place during a short period in prenatal and postnatal development. These interactions are not completely understood, and hence primary prevention remains an elusive goal. We argue that primary-care physicians, paediatricians, and specialists lack knowledge of the role of atopy in early life in the development of persistent asthma in children. In this review, we discuss how early identification of children at high risk is feasible on the basis of available technology and important for potential benefits to the children. Identification of an asthmatic child's atopic status in early life has practical clinical and prognostic implications, and sets the basis for future preventative strategies.

Maternal stress and depression and the lateralisation of infant cradling.

BACKGROUND: Studies show that 65-85% of mothers cradle their infants to the left side of their body, but that this bias changes with maternal mood and stress. The present study examines the hypothesis that maternal stress and depression status will influence the cradling bias differentially. METHOD: As part of a larger study on mother-infant interaction, mothers (N = 79) were asked to pick up and briefly hold their children in their arms (44 boys, 35 girls; mean age 7.2 months, range 3 to 14 months). RESULTS: Results indicated that 86% of mothers who were neither stressed nor depressed cradled to the left and 14% to the right. Comparing the cradling side of stressed mothers with those who were neither stressed nor depressed, more in the former group showed right-sided cradling. In contrast, mothers who were just depressed preferred to cradle to the left. CONCLUSION: The lack of a left-sided cradling bias might be due to stress rather than depression experienced by mothers. Furthermore, this study provides evidence that the state of maternal mental health might be indicated by the side on which they cradle their child preferentially.

How well are general practice trainees prepared for paediatric prescribing?

AIMS AND METHODOLOGY: We invited 232 General Practice Trainees to complete an on-line questionnaire to assess how they rated their training for the task of paediatric prescribing and therapeutics in the community. RESULTS: Of the 166 (71%) respondents who completed the questionnaire, 26.5% recalled specific teaching about paediatric prescribing and 59.6% covering one or more relevant topic during their undergraduate years. Undertaking a paediatric post during vocational training was associated with greater prescribing confidence (P < 0.001); however, 35% of respondents were not intending to undertake such a post. CONCLUSION: This study suggests that many GP trainees perceive their paediatric prescribing training as inadequate.

Nasal epithelial cells as surrogates for bronchial epithelial cells in airway inflammation studies.

The nose is an attractive source of airway epithelial cells, particularly in populations in which bronchoscopy may not be possible. However, substituting nasal cells for bronchial epithelial cells in the study of airway inflammation depends upon comparability of responses, and evidence for this is lacking. Our objective was to determine whether nasal epithelial cell inflammatory mediator release and receptor expression reflect those of bronchial epithelial cells. Paired cultures of undifferentiated nasal and bronchial epithelial cells were obtained from brushings from 35 subjects, including 5 children. Cells were subject to morphologic and immunocytochemical assessment. Mediator release from resting and cytokine-stimulated cell monolayers was determined, as was cell surface receptor expression. Nasal and bronchial cells had identical epithelial morphology and uniform expression of cytokeratin 19. There were no differences in constitutive expression of CD44, intercellular adhesion molecule-1, alphavbeta3, and alphavbeta5. Despite significantly higher constitutive release of IL-8, IL-6, RANTES (regulated on activation, normal T cell expressed and secreted), and matrix metalloproteinase (MMP)-9 from nasal compared with bronchial cells, the increments in release of all studied mediators in response to stimulation with IL-1beta and TNF-alpha were similar, and there were significant positive correlations between nasal and bronchial cell secretion of IL-6, RANTES, vascular endothelial growth factor, monocyte chemoattractant protein-1, MMP-9, and tissue inhibitor of metalloproteinase-1. Despite differences in absolute mediator levels, the responses of nasal and bronchial epithelial cells to cytokine stimulation were similar, expression of relevant surface receptors was comparable, and there were significant correlations between nasal and bronchial cell mediator release. Therefore, nasal epithelial cultures constitute an accessible surrogate for studying lower airway inflammation.

Interleukin 18 receptor 1 gene polymorphisms are associated with asthma.

The interleukin 18 receptor (IL18R1) gene is a strong candidate gene for asthma. It has been implicated in the pathophysiology of asthma and maps to an asthma susceptibility locus on chromosome 2q12. The possibility of association between polymorphisms in IL18R1 and asthma was examined by genotyping seven SNPs in 294, 342 and 100 families from Denmark, United Kingdom and Norway and conducting family-based association analyses for asthma, atopic asthma and bronchial hyper-reactivity (BHR) phenotypes. Three SNPs in IL18R1 were associated with asthma (0.01131 < or = P < or = 0.01377), five with atopic asthma (0.00066 < or = P < or = 0.00405) and two with BHR (0.01450 < or = P < or = 0.03203) in the Danish population; two SNPs were associated with atopic asthma (0.00397 < or = P < or = 0.01481) and four with BHR (0.00435 < or = P < or = 0.03544) in the UK population; four SNPs showed associations with asthma (0.00015 < or = P < or = 0.03062), two with atopic asthma (0.01269 < or = P < or = 0.04042) and three with BHR (0.00259 < or = P < or = 0.01401) in the Norwegian population; five SNPs showed associations with asthma (0.00005 < or = P < or = 0.03744), five with atopic asthma (0.00001 < or = P < or = 0.04491) and three with BHR (0.03568 < or = P < or = 0.04778) in the combined population. Three intronic SNPs (rs1420099, rs1362348 and rs1974675) showed replicated association for at least one asthma-related phenotype. These results demonstrate significant association between polymorphisms in IL18R1 and asthma.

A prospective study of phrenic nerve damage after cardiac surgery in children.

OBJECTIVE: To gather detailed data on the incidence of phrenic nerve damage (PND) following cardiac surgery in children, the risk factors for its development, its effect on morbidity and its prognosis. DESIGN: Prospective electrophysiological measurement of phrenic nerve latency in 310 children before and after cardiac surgery. SETTING: Tertiary paediatric cardiac surgical centre. MEASUREMENTS AND RESULTS: Our findings were fourfold. Firstly, the incidence of PND in our group of patients was 20%, significantly higher than estimates using indirect methods of assessment. Secondly, PND increased the duration of ventilation by a median of 76 h (20 vs. 96 h; p<0.001), and late post-operative deaths (before hospital discharge) occurred in 12.9% of patients compared to 2.4% among patients with a normal post-operative phrenic latency. Thirdly, the risk factors that were independently predictive of the development of PND were the site of the surgery and the patient's age. Patients who required surgery at both the lung hilum and the pericardium were more likely to develop PND than patients with only one of those sites, or when neither was involved, and children less than 18 months old were more likely to develop PND than older children. Lastly, the natural history of PND following surgery appears to be good. In our follow-up to 3 months, approximately one third recovered within 1 month and a further third (overall) recovered by 3 months. CONCLUSIONS: We conclude that the incidence of PND is much higher than currently recognised, and has a very significant effect on post-operative morbidity and mortality. Most children who survive the post-operative period will recover nerve function within 3 months.