The effect of age on the relationship between birth order and immunoglobulin E sensitization.

BACKGROUND: An association between birth order and IgE sensitization or allergic diseases has been reported in many studies. OBJECTIVE: To assess the effect of age on the relationship between reduced IgE sensitization and increased birth order and to test the hypothesis that this would decline with increasing age. METHODS: As part of a birth cohort study, IgE sensitization to common allergens was determined by skin prick testing at ages 6 and 12 months, 6 and 11 years. RESULTS: The original cohort numbered 253 individuals of whom 96 (38%) were first born. Compared with individuals with older siblings, first-born individuals had increased IgE sensitization at 6 (odds ratio (OR) 2.4 [95% confidence interval (CI) 1.0, 6.3], P=0.05, n=197) and 12 months of age (OR 6.7 [1.7, 25.0] P=0.002, n=172) and at 6 years of age (OR 2.3 [1.0, 5.6] P=0.05, n=113) but not at 11 years of age (OR 1.2, P>0.4, n=182). When age at onset of IgE sensitization was considered (n=61), 16 had infant onset IgE sensitization (nine were first born), 24 had early childhood onset IgE sensitization (nine first born) and 21 had late childhood onset IgE sensitization (two first born), P=0.0016. Further analysis revealed a similar pattern for children with older brothers (P=0.0097) but not older sisters (P=0.5). CONCLUSIONS: These findings indicated that having an older brother delays the onset of IgE sensitization but may not prevent IgE sensitization per se. The apparent protective effect of older siblings on allergic diseases reported elsewhere might involve delaying the onset of IgE sensitization.

Determinants of airway responsiveness to histamine in children.

Increased airway responsiveness (AR) is associated with asthma, but not all individuals with increased AR have asthma. The aim of this study was to identify factors, other than physician-diagnosed asthma (PDA), which are associated with increased AR. In a longitudinal study, data were collected on atopy and lower respiratory tract illness (LRTI) in infancy, and AR (expressed as dose-response slope (DRS)), atopy, tobacco-smoke exposure and PDA in childhood. At age 6 yrs, DRS was assessed in 102 children, of whom 22 (22%) had PDA; the corresponding figures at 11 yrs of age were 176 and 29 (15%). At age 6 yrs, DRS was significantly associated with PDA, current atopy and parental smoking (n = 83). At age 11 yrs, DRS was significantly associated with PDA, current atopy and LRTI in the first six months (n = 75). There was a significant positive interaction between atopy at age 12 months and PDA age 11 yrs. In conclusion, these data suggest that factors other than asthma or atopy may determine the level of airway responsiveness in children. In children with asthma, airway responsiveness may be influenced by the early onset of atopy. The current findings may explain the inconsistent relationship between airway responsiveness and asthma.

beta2 adrenoceptor Arg16Gly polymorphism, airway responsiveness, lung function and asthma in infants and children.

BACKGROUND: We have previously reported a relationship between increased airway responsiveness (AR) in infancy and reduced childhood lung function. OBJECTIVE: The current study aimed to determine whether the Arg16Gly polymorphism of the beta2 adrenoceptor (beta2AR) gene was important to this relationship. METHODS: A cohort that initially numbered 253 individuals underwent assessments of AR and lung function aged 1 month, 6 and 11 years; genotyping for polymorphisms of the beta(2)AR was performed. RESULTS: At 1 month of age, the genotype homozygous Arg16 (n=24) was associated with a mean increase in log dose-response slope (AR) of 0.27 [95% confidence interval (CI) 0.07, 0.49] compared with the genotype homozygous Gly16 (n=58), P=0.01. At 11 years of age, the genotype homozygous Arg16 (n=35) was associated with a mean reduction in the percentage of forced expiratory volume in 1 s of 5.3% [95% CI 0.3, 10.2] compared with the genotype homozygous Gly16 (n=65), P=0.03. There was no association between the Arg16Gly polymorphism and atopy or diagnosed asthma. However, nine of 69 individuals with the genotype homozygous Gly16 were admitted to hospital with asthma compared with five out of 111 individuals with the remaining genotypes (P<0.05). CONCLUSION: The Arg16Gly polymorphism may be important to the association between increased AR in infancy and reduced lung function in childhood and may also be a determinant of asthma severity in children but not asthma per se.

Airway responsiveness in early infancy predicts asthma, lung function, and respiratory symptoms by school age.

Asthma is the most common chronic childhood disease in developed nations. Little is known about the relationship between airway responsiveness in infancy and the development of asthma later in life. The relationship of airway responsiveness at 1 mo with asthma, atopy, lower respiratory symptoms, and lung function at 6 yr of age was investigated prospectively in 95 white children from a randomly ascertained birth cohort. Baseline spirometry, airway responsiveness to histamine, and skin reactivity to common allergens were assessed at the age of 1 mo and 6 yr. Total serum immunoglobulin E (IgE) was measured from cord blood and at 6 yr. Blood eosinophil counts were measured at 6 yr only. Family, symptom, and exposure histories at both time points were derived from questionnaire data. Independently of the other factors assessed, increased airway responsiveness at 1 mo was significantly associated with the following parameters measured at six yr: decreased FEV(1) (p < 0.001); decreased FVC (p < 0.001); physician-diagnosed asthma (p < 0.001); and lower respiratory tract symptoms (p < 0.05). None of the other physiologic factors measured in infancy showed such consistent associations with important clinical and physiologic outcomes at age 6. These data suggest that airway responsiveness in early life defines a functional state that is associated with abnormal airway function, lower respiratory symptoms, and the emergence of asthma by 6 yr of age.

Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study.

Long-term use of high-dose corticosteroids often results in bone loss, which may lead to osteoporosis-related fractures. This was a multicenter, double-blind study in which 290 ambulatory men and women receiving high-dose oral corticosteroid therapy (prednisone > or = 7.5 mg/day or equivalent) for 6 or more months were randomized to receive placebo, risedronate 2.5 mg/day, or risedronate 5 mg/day for 12 months. All patients received calcium 1 g and vitamin D 400 IU daily. The primary endpoint was lumbar spine bone mineral density (BMD) at month 12. Additional measurements included BMD at the femoral neck and trochanter and the incidence of vertebral fractures. Overall, there were statistically significant treatment effects on BMD at 12 months at the lumbar spine (p < 0.001), femoral neck (p = 0.004), and trochanter (p = 0.010). Risedronate 5 mg increased BMD at 12 months by a mean (SEM) of 2.9% (0.49%) at the lumbar spine, 1.8% (0.46%) at the femoral neck, and 2.4% (0.54%) at the trochanter, whereas BMD was maintained only in the control group. Although not powered to show fracture efficacy, we observed a reduction in the incidence of vertebral fractures of 70% in the combined risedronate treatment groups, relative to placebo (p = 0.042). Risedronate was well tolerated, had a good safety profile, and was not associated with gastrointestinal adverse events. We conclude that risedronate increases BMD and potentially reduces the incidence of vertebral fractures in patients with corticosteroid-induced osteoporosis.

Dose-proportional pharmacokinetics of risedronate on single-dose oral administration to healthy volunteers.

Risedronate is a pyridinyl bisphosphonate approved for the treatment of Paget's disease (US-FDA) and in development for the treatment and prevention of osteoporosis. This study examined risedronate pharmacokinetics and tolerability after oral administration using a randomized, double-blind, parallel-group design. Healthy male and female volunteers (n = 22-23 subjects per dose) received a single oral dose of 2.5, 5, or 30 mg risedronate. Serum and urine samples were collected for 72 and 672 hours, respectively, and risedronate concentrations were determined by ELISA. Safety was evaluated by monitoring adverse events, clinical laboratory measurements, vital signs, and electrocardiograms. Mean Cmax (0.41, 0.94, and 5.1 ng/mL for 2.5, 5, and 30 mg, respectively), AUC (1.8, 3.9, and 21 ng.h/mL for 2.5, 5, and 30 mg, respectively), and urinary excretion (22, 63, and 260 micrograms for 2.5, 5, and 30 mg, respectively) were dose proportional, and there were no significant differences in tmax or CLR among the three doses. All doses were well tolerated; no serious adverse events occurred, and all but one of the adverse events were mild or moderate in severity. There was no evidence of an acute phase reaction occurring after oral administration of risedronate.

Association of FcepsilonR1-beta polymorphisms with asthma and associated traits in Australian asthmatic families.

BACKGROUND: Asthma is a genetically complex disease, and is characterized by elevated serum immunoglobulin E (IgE) levels, elevated blood eosinophil counts and increased airway responsiveness. Polymorphisms in the beta subunit of the high affinity receptor for IgE (FcepsilonR1-beta) have been previously associated with these phenotypes and with an increased risk of asthma. OBJECTIVE: To investigate the association of all known bi-allelic polymorphisms in FcepsilonR1-beta to asthma and quantitative traits associated with asthma in a selected sample of Australian asthmatic children and their nuclear families. METHODS: Australian Caucasian nuclear families (n = 134 subjects) were recruited on the basis of a child proband with current, severe, symptomatic asthma. The quantitative traits assessed included serum levels of total IgE and specific IgE to house dust mite and mixed grass, blood eosinophil counts and the dose-response slope of the forced expiratory volume in 1 s to histamine provocation. RESULTS: Neither the Leu181 nor the E237G mutations were detected in this population. Allele B of RsaI intron 2 (RsaI_in2*B) was significantly associated with physician-diagnosed asthma (ever) (P = 0.002). Alleles of both the RsaI_in2 and RsaI exon 7 (RsaI_ex7) polymorphisms were significantly associated with loge total serum IgE levels and the combined RAST index. RsaI_ex7 was also associated with loge blood eosinophil counts. These associations were independent of age, sex and familial correlations. CONCLUSION: This study supports a role for the FcepsilonR1-beta gene or a nearby gene in the pathogenesis of asthma.

Linkage of chromosome 5q and 11q gene markers to asthma-associated quantitative traits in Australian children.

Asthma is a genetically complex disease, and the investigation of putative linkages to candidate loci in independent populations is an important part of the gene discovery process. This study investigated the linkage of microsatellite markers in the 5q and 11q regions to asthma-associated quantitative traits in 121 Australian Caucasian nuclear families. The families were recruited on the basis of a child proband: a cohort of 95 randomly recruited families of unselected probands (n = 442 subjects) and a cohort of 26 families of probands selected on the basis of severe symptomatic asthma (n = 134 subjects). The quantitative traits assessed included serum levels of total IgE and specific IgE to house dust mite and mixed grass, blood eosinophil counts, and the dose-response slope (DRS) of FEV1 to histamine provocation. Multipoint linkage analysis using Haseman-Elston sib-pair methods provided evidence of significant linkage between the chromosome 5q markers and loge total serum IgE levels, specific serum IgE levels, and loge blood eosinophil counts. The chromosome 11q markers showed evidence of significant linkage to specific serum IgE levels. Neither region demonstrated significant linkage to the loge DRS to histamine. Phenotypes were residualized for age and sex. These data are consistent with the existence of loci regulating asthma-associated quantitative traits in both the 5q31-33 and 11q13 chromosomal regions.

A polymorphism of the CC16 gene is associated with an increased risk of asthma.

Several quantitative traits associated with the asthma phenotype have been linked to markers on chromosome 11q13, although the gene responsible has yet to be well established. The gene for Clara cell secretory protein (CC16) is an ideal candidate for involvement in an inherited predisposition to asthma because of its chromosomal location, the role of the CC16 protein in controlling airway inflammation, and differences in levels of the protein between asthmatics and healthy controls. All three CC16 exons were screened in an unselected population of 266 subjects from 76 families and a cohort of 52 severely asthmatic children. A combination of single strand conformational polymorphism (SSCP) analysis, heteroduplex analysis, DNA sequencing, and restriction digestion was used. Mutation detection methods identified an adenine to guanine substitution in the CC16 gene at position 38 (A38G) downstream from the transcription initiation site within the non-coding region of exon 1. In the unselected population, 43.6% were homozygous for the polymorphic sequence (38GG) and 46.2% were heterozygous (38AG). All the asthmatic and unaffected children from both populations were selected for an unmatched case control analysis consisting of 67 asthmatic and 46 unaffected subjects. Those homozygous for the published sequence (38AA) had a 6.9-fold increased risk of developing asthma (p=0.049) and heterozygotes (38AG) a 4.2-fold increased risk (p=0.028). Modelling of genotype as a continuous covariate indicated evidence of a significant linear trend across the three genotypes (odds ratio=2.84 per unit increase in genotype code, p=0.018). These associations were independent of age, gender, and tobacco smoke exposure. These data and the known anti-inflammatory role of CC16 in the respiratory tract suggest that alteration to the gene at position 38 may contribute to asthma.

Association of polymorphisms within the tumour necrosis factor (TNF) genes and childhood asthma.

BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a potent modulator of immune and inflammatory responses, and has been implicated in a variety of autoimmune diseases, including asthma. Increased levels of TNFalpha have been detected in both sputa and bronchoalveolar lavage fluid of asthmatic subjects during acute attacks. Interindividual variation in TNFalpha levels may be genetically determined and polymorphisms within the TNF genes and nearby HLA Class II region have been associated with differences in TNFalpha production. OBJECTIVE: To investigate the association of differences in asthma-related phenotypes with two biallelic polymorphisms: a G to A substitution at position - 308 of the TNFalpha gene promoter (TNF1 and TNF2 alleles) and an NcoI polymorphism in the first intron of the lymphotoxin alpha gene (LT-alpha*1 and LT-alpha*2 alleles). METHODS: The regions of interest were amplified from genomic DNA using specific primers and PCR. Dot blot analysis was used for genotyping individuals for the TNFalpha - 308 polymorphism, while restriction enzyme digestion was used for genotyping individuals for the LT-alpha gene NcoI polymorphism. A case-control analysis was then performed on 74 asthmatic and 50 non-asthmatic unrelated children for each polymorphism. RESULTS: The TNFalpha - 308 TNF1 allele was present at a significantly higher frequency in cases than controls (OR= 2.4, P=0.003), and homozygosity for the TNF1 allele was associated with a fivefold increased risk of physician diagnosed asthma relative to the other genotypes (OR = 5.23, P = 0.004). The LT-alpha*2 allele showed similar associations, including an approximately fivefold higher risk of physician diagnosed asthma for LT-alpha*2 homozygotes (OR = 4.89, P = 0.019). Evidence of a significant linear trend in asthma risk across the three genotypes was found for both polymorphisms. CONCLUSION: These results suggest an important role for the TNFalpha gene or a linked locus in an inherited asthma diathesis.

Compliance with inhaled asthma medication in preschool children.

BACKGROUND: Previous studies have shown poor compliance with regular drug therapy in children and adults with asthma. In preschool children the parents supervise and are responsible for drug administration, but little is known of compliance in this group. In addition, there are few data on the patterns of drug use of inhaled prophylactic asthma therapy or of the relation between compliance and symptom control. A study was undertaken to address these issues with the hypothesis that parental supervision would result in good compliance. METHODS: The subjects were 29 asthmatic children aged 15 months to five years already established on inhaled prophylactic medication delivered through a large volume spacer. The prescribed drug regimens varied between subjects. This was an observational study using an electronic inhaler timer device to record the date and time of each actuation of the aerosol canister. Diary cards were used for parallel recording of symptoms and parentally reported compliance with a drug regimen. RESULTS: Variable and generally poor compliance was demonstrated with a median of 50% of study days with full compliance (subject range 0-94%) and an overall median of 77% of prescribed doses of therapy taken during the study period. No relation was found between frequency of prescribed regimen and good compliance. Day care was associated with poorer compliance. No relation between good compliance and low symptom scores was found. CONCLUSION: Compliance with inhaled prophylactic therapy is poor in preschool children with asthma whose medication is administered under parental supervision.

Measured bronchodilator use in preschool children with asthma.

OBJECTIVE: To investigate how parents use bronchodilator treatment for relief of symptoms when treating their asthmatic preschool children. DESIGN: A commercial electromechanical timer device was attached to a large volume spacer to record the time and date of each use of inhaled bronchodilator over two months. The recorded time and dates were compared with symptoms noted in an asthma diary card. SETTING: Large paediatric teaching hospital in Glasgow. SUBJECTS: 29 preschool children with moderately severe asthma attending a specialist paediatric asthma clinic. MAIN OUTCOME MEASURES: Inhaler use measured by the timer device; symptoms and inhaler use recorded by parents in a daily asthma diary. RESULTS: Satisfactory data were obtained in 22 of the 29 children; the median number of study days was 53 (range 18-77). Asthmatic symptoms were recorded on a median of 30 (3-77) days. Bronchodilator was used on a median of 19 (2-73) days, or on 63% (7-100%) of days when symptoms occurred. The median number of puffs used in a day was 1 (range 0-100) and was significantly related to symptom severity in only 14 of the 22 children. In only two of the 22 children was bronchodilator given more frequently than four hourly, and only five children ever used more than 12 puffs a day. CONCLUSIONS: The frequency of parental administration of bronchodilator treatment was variable and not closely related to the parent's record of symptom severity. Parents often recorded symptoms in their children but did not treat them.

Hazards of ketoconazole therapy in testotoxicosis.

An eight-year-old boy with Leydig cell hyperplasia (testotoxicosis) was admitted with a three-day history of rash, vomiting and diarrhoea, followed by acute onset of breathlessness and confusion. He was shocked, with liver cell and renal failure, erythematous rash and severe interstitial pneumonitis. He had been treated with ketoconazole for four years prior to admission, receiving 1200mg daily during the preceding year. Cessation of ketoconazole therapy was associated with full clinical recovery but relapse of testotoxicosis. Ketoconazole was reintroduced cautiously at a lower dose, with no ill-effect, and reasonable control of testotoxicosis. We conclude that this boy's illness, including the interstitial pneumonitis, represented a reaction to ketoconazole which was dose-related rather than idiosyncratic.

Flexible bronchoscopy under 10 kg.

We report 35 bronchoscopies performed in 27 post-neonatal subjects weighing less than 10 kg using an Olympus BC3F20 (3.5 mm diameter) bronchoscope. Twenty-three procedures were performed primarily for investigation of airway anatomy and 12 primarily for broncho-alveolar lavage. Mild oxygen desaturation responsive to increased O2 administration was common. Major complications were infrequent with two children developing lower respiratory tract infection and one patient requiring ventilation overnight. The diagnostic yield was high with 76% of studies in children suspected of airway anomalies proving positive. We conclude that bronchoscopy in this age group is well tolerated and identifies a significant number of abnormalities.

Somatosensory evoked potentials and outcome in perinatal asphyxia.

Somatosensory evoked potentials (SEP) can be measured in the term newborn infant and given an index of function in the areas of the brain most likely to be damaged in perinatal asphyxia. We studied the median nerve SEP in 30 asphyxiated term infants over the course of their encephalopathy and until discharge from the neonatal unit. Three types of response were noted: normal waveform, abnormal waveform, or absence of cortical response. Follow up of the survivors was undertaken at a mean age of 12 months by means of a Griffiths' assessment and neurological examination. Nine infants died of their asphyxial illness and one of spinal muscular atrophy. Of the 20 survivors, three have cerebral palsy, four have minor abnormalities, and 13 are neurodevelopmentally normal. There was a close correlation between outcome and SEP. All 13 infants with normal outcome had normal SEP by 4 days of age, whereas those with abnormal or absent responses beyond 4 days had abnormalities at follow up.

Measuring compliance with inhaled medication in asthma.

Using an electronic inhaler timer device (Nebulizer Chronolog), compliance with the prescribed frequency of inhaled prophylactic medication in 14 asthmatic children was measured. Underuse occurred in 55% of study days while overuse occurred in only 2%. Such devices provide an important new tool for investigating inhaled drug compliance.

Cadmium-induced bone loss: increased susceptibility in female beagles after ovariectomy.

Bone resorption, as measured by release of bone 45Ca, was significantly increased in elderly female beagles within 96 h of exposure to 15 mg/l cadmium in drinking-water. The 45Ca response was greater in ovariectomized animals than in sham-operated controls and was not mediated by changes in calciotropic hormone concentrations. Mean blood cadmium concentrations were 3-8 micrograms/l during the earliest bone resorption response and 13-15 micrograms/l at the end of the study. During seven months of cadmium exposure, bone mineral densities decreased most in the ovariectomized animals exposed to cadmium: -15.4 +/- 4.3% for the tibia distal end and -7.2 +/- 1.2% for the lumbar vertebrae (L2-L4) (mean +/- SE, n = 4). The results indicate that cadmium may act directly on bone and that postmenopausal women exposed to cadmium in industry or via cigarette smoke may be at increased risk of cadmium-induced bone loss. They also support a direct role of cadmium in the etiopathology of itai-itai disease among postmenopausal women in Japan.

Somatosensory evoked potentials in the term newborn.

Median nerve somatosensory evoked potentials (SEPs) were recorded from surface electrodes in 40 healthy term infants (range 36.5-43 weeks postmenstrual age). Electrical stimulation at 5 Hz was used, averaging the response to several runs of 1024 stimuli to each median nerve, bandpass 10-3000 Hz, sweeptime 100 msec. Identifiable potentials were collected over the cervical cord on all runs in all 40 infants and from the cortex in at least some runs in 39 out of 40 infants. The cervical response showed little variation and consisted of a clear negative wave with up to 3 peaks, mean latency of the largest 10.2 +/- 0.7 msec, followed by a positive deflection. The cortical response was very variable in form and latency between infants and to a lesser degree within infants. Four types of cortical wave form were found, symmetrical, asymmetrical, plateau and M shaped, of increasing complexity. In 11% of trials the response was absent or indistinct but could usually be uncovered by alteration in stimulus frequency or intensity. In the whole group, the mean latency for N1 was 30.0 +/- 6.8 msec and for the central conduction time 19.8 +/- 6.5 msec. Significant differences were found between the 4 cortical wave forms in the main variables measured, which gave support for form S being the most primitive and form M the most mature response.

The use of a calcium-channel blocker, nicardipine, for severely asphyxiated newborn infants.

A continuous infusion of nicardipine was given to four severely asphyxiated fullterm infants who were at high risk for adverse outcome and had abnormal cerebral Doppler haemodynamic studies. The heart rate increased in all four infants and mean arterial blood pressure (MAP) fell in three. Two infants had a sudden and marked fall in MAP, together with severe impairment of skin blood-flow and a concurrent fall in cerebral blood-flow velocity. The serum level of nicardipine was less than 40ng/mL in all cases. The use of nicardipine, and possibly other calcium-channel blockers, may be associated with marked hypotension, and if there is no cerebral autoregulation, may cause further cerebral hypoperfusion, so use of these drugs in asphyxiated newborn infants should only be attempted if blood pressure is carefully monitored.