Influence of anemia and BMI on prognosis of laryngeal squamous cell carcinoma: Development of an updated prognostic model.

OBJECTIVE: evaluating the impact of anemia and body mass index (BMI) on survival, and development of a prognostic model for overall survival for patients with laryngeal squamous cell carcinoma (LSCC). MATERIALS AND METHODS: A retrospective cohort study was performed including all consecutive patients with LSCC diagnosed and treated at the Erasmus Medical Center between January 2006 and December 2013. Patient- and tumor-specific data were collected using data from the Netherlands Comprehensive Cancer Organization and supplemented with data from patient records available in the Erasmus MC. All comorbidities were scored at the time of diagnosis. RESULTS: in total 788 patients were included. Mean follow-up time was 50 months (SD: ±30), during which 298 patients (37.8%) died. In both univariate and multivariate analysis BMI and anemia were significant predictors for overall survival. Multivariate analysis was performed using known predictors such as age, TNM-stage and comorbidity (ACE-27). The hazard ratio of anemia was 1.41 (95% CI: 1.05-1.90) and of BMI was 0.97 (95% CI: 0.94-0.99). BMI had an inverse association with overall survival in both univariate and multivariate survival analysis. Updating and validating an existing prognostic model with addition of anemia and BMI enhanced the performance of the prognostic model (C-statistic) from 0.77 (95% CI: 0.74-0.79) to 0.79 (95% CI: 0.77-0.82). CONCLUSION: anemia and BMI are predictors of overall survival for LSCC, independent of other known predictors of overall survival. Adding anemia and BMI to an existing prognostic model provides better prediction of overall survival.

Adjuvant radiotherapy in sinonasal mucosal melanoma: A retrospective analysis.

OBJECTIVES: Evaluation of outcome after curative treatment for sinonasal mucosal melanoma focused on the effect of adjuvant radiotherapy on recurrence and survival. DESIGN: Retrospective chart analysis. SETTING: Tertiary referral hospital. PARTICIPANTS: Fifty-one patients with primary sinonasal mucosal melanoma who underwent surgical resection with curative intention between 1980 and 2016 at Erasmus Medical Center, Rotterdam. MAIN OUTCOME MEASURES: Patients were categorised into 2 groups: surgery alone and surgery with adjuvant radiotherapy. Log-rank test was used to compare rates of recurrence and survival between treatment groups. Predictors for treatment modality, recurrence and survival were assessed with multivariate statistical analysis. RESULTS: Of all patients, 23.5% developed local recurrence and 47.1% developed distant metastasis. Estimated 5-year disease-free survival was 25.2%, and 5-year overall survival (OS) was 38.1%. Forty-three patients (84.3%) were treated with post-operative radiotherapy. Patients who underwent surgery with adjuvant radiotherapy presented more often with high tumour stage, tumour involving multiple sites and positive margins. Post-operative radiotherapy seemed to be associated with better local control (P = .549). No effect was found on occurrence of distant metastasis and OS. Positive margin status was an independent negative predictor for distant metastasis-free survival and overall survival. CONCLUSIONS: Our treatment outcomes are consistent with literature. Post-operative radiotherapy seems to be associated with improved local control despite advanced disease and positive margin status in this treatment group.

Significant and variable linear polarization during the prompt optical flash of GRB 160625B.

Newly formed black holes of stellar mass launch collimated outflows (jets) of ionized matter that approach the speed of light. These outflows power prompt, brief and intense flashes of γ-rays known as γ-ray bursts (GRBs), followed by longer-lived afterglow radiation that is detected across the electromagnetic spectrum. Measuring the polarization of the observed GRB radiation provides a direct probe of the magnetic fields in the collimated jets. Rapid-response polarimetric observations of newly discovered bursts have probed the initial afterglow phase, and show that, minutes after the prompt emission has ended, the degree of linear polarization can be as high as 30 per cent-consistent with the idea that a stable, globally ordered magnetic field permeates the jet at large distances from the central source. By contrast, optical and γ-ray observations during the prompt phase have led to discordant and often controversial results, and no definitive conclusions have been reached regarding the origin of the prompt radiation or the configuration of the magnetic field. Here we report the detection of substantial (8.3 ± 0.8 per cent from our most conservative simulation), variable linear polarization of a prompt optical flash that accompanied the extremely energetic and long-lived prompt γ-ray emission from GRB 160625B. Our measurements probe the structure of the magnetic field at an early stage of the jet, closer to its central black hole, and show that the prompt phase is produced via fast-cooling synchrotron radiation in a large-scale magnetic field that is advected from the black hole and distorted by dissipation processes within the jet.

Postoperative value of serum squamous cell carcinoma antigen as a predictor of recurrence in sinonasal inverted papilloma.

OBJECTIVES: Sinonasal inverted papilloma (IP) has several unfavourable characteristics and therefore requires careful monitoring. The goal of this study was to identify whether serum squamous cell carcinoma antigen (SCCa) could predict IP recurrence. DESIGN: A retrospective cohort study. SETTING: Department of otolaryngology/head and neck surgery, Erasmus Medical Centre, Rotterdam, the Netherlands. PARTICIPANTS: One hundred and thirty patients with IP treated at our centre with SCCa measurements available were included. MAIN OUTCOME MEASUREMENTS: Follow-up of patients with IP since 2005, recurrence was defined as new disease within primary localisation at least 3 months after adequate surgical removal. We analysed the association between IP recurrence and serum SCCa values measured preoperatively, postoperatively and during follow-up. RESULTS: Preoperative SCCa values or values measured during follow-up were not associated with risk of recurrence. Postoperative SCCa was positively associated with the risk of recurrence (P < 0.001). Postoperative SCCa had a good discriminative ability for the identification of recurrence with an area under the curve of 80.9%. CONCLUSION: Postoperative SCCa is strongly associated with risk of recurrence. This might help the surgeon in the postoperative setting by identifying high-risk patients and planning follow-up strategy tailored to the individual patient.

Identifying at diagnosis the vestibular schwannomas at low risk of growth in a long-term retrospective cohort.

OBJECTIVES: Identification at time of diagnosis of those vestibular schwannomas that will not grow. DESIGN: Retrospective cohort study of consecutive patients diagnosed with a sporadic vestibular schwannoma that were entered in the wait-and-scan protocol. SETTING: Academic referral centre. PARTICIPANTS: The study group contained 155 patients with a sporadic vestibular schwannoma first seen in the full 8-year period 2000-2007: continual wait-and-scan (n = 89) and initial wait-and-scan until intervention (n = 66). MAIN OUTCOME MEASURES: Tumour growth, defined as more than 2 mm linear difference in any plane between the diagnostic MRI-scan and the last available scan, was related to clinical parameters at diagnosis: localisation of the tumour (solely intracanalicular versus cisternal extension), sudden sensorineural hearing loss, sensorineural hearing loss longer than 2 years and vertigo/instability. RESULTS: Hearing loss longer than 2 years and an entirely intracanalicular localisation were associated with no tumour growth by univariate and multivariate Cox analysis. Combining both factors at time of diagnosis resulted in a group with low risk of growth (n = 36, median follow-up of 6.2 years) with a Hazard Ratio for growth of 0.37 (95% CI, 0.19-0.69). This subgroup is about 25% of the wait-and-scan population. Thirty-one percent showed growth, while in the remaining higher risk group of 119 patients 62% showed growth. For the growing schwannomas, the median time for growth becoming manifest is 1.9 years after diagnostic MRI. CONCLUSIONS: In this study on vestibular schwannoma patients that start in a wait-and-scan protocol, about a quarter may be set apart having a low risk for growth. These patients at diagnosis combine a history of hearing loss longer than 2 years and a fully intracanalicular schwannoma. They seem to be not needed yearly MRI checks.

Zenker's diverticulum: Rotterdam experience.

Different surgical techniques exist for the treatment of Zenker's diverticulum (ZD), of which minimally invasive techniques have become the standard. We reviewed our experience with management and treatment of ZD and sought to determine what type of treatment is most effective and efficient. We selected patients who underwent treatment for ZD between January 2004 and January 2014 at our tertiary referral center. All procedures were performed by ENT surgeons. The medical records were reviewed for pre- and intraoperative characteristics and follow-up. Of our 94 patients (58 male, 36 female), 75 underwent endoscopic cricopharyngeal myotomy (42 stapler, 33 laser) and 6 received treatment via transcervical approach. 13 interventions were aborted. Mean operating time was 49.0 min for stapler, 68.3 for laser and 124.0 for the transcervical approach. Its respective median post-operative admission durations were 2.0, 3.0 and 3.0 days. After the first treatment, of the 75 endoscopic procedures, 45 patients (23 stapler, 22 laser) had complete symptom resolution. In the transcervical group 4 (67 %) patients were symptom free and one patient died of complications. In the endoscopically treated patients, ten complications occurred, of which 8 G1 and 2 G2 (Clavien Dindo classification). In the transcervical group 2 complications occurred, 1 G3b and 1 G5. Both endoscopic techniques provide efficient management of Zenker's diverticulum with the stapler-assisted modality providing a shorter surgery duration and hospital admission. Although there is no significant difference in terms of complications or recurrence rates for both endoscopic techniques, it seems that stapler patients are at higher risk of having a re-intervention and of having more severe complications.

Swings between rotation and accretion power in a binary millisecond pulsar.

It is thought that neutron stars in low-mass binary systems can accrete matter and angular momentum from the companion star and be spun-up to millisecond rotational periods. During the accretion stage, the system is called a low-mass X-ray binary, and bright X-ray emission is observed. When the rate of mass transfer decreases in the later evolutionary stages, these binaries host a radio millisecond pulsar whose emission is powered by the neutron star's rotating magnetic field. This evolutionary model is supported by the detection of millisecond X-ray pulsations from several accreting neutron stars and also by the evidence for a past accretion disc in a rotation-powered millisecond pulsar. It has been proposed that a rotation-powered pulsar may temporarily switch on during periods of low mass inflow in some such systems. Only indirect evidence for this transition has hitherto been observed. Here we report observations of accretion-powered, millisecond X-ray pulsations from a neutron star previously seen as a rotation-powered radio pulsar. Within a few days after a month-long X-ray outburst, radio pulses were again detected. This not only shows the evolutionary link between accretion and rotation-powered millisecond pulsars, but also that some systems can swing between the two states on very short timescales.

Pre- and post-natal exposure to antibiotics and the development of eczema, recurrent wheezing and atopic sensitization in children up to the age of 4 years.

BACKGROUND: Little data are available on the relationship between indirect antibiotic exposure of the child in utero or during lactation and allergic diseases. On the other hand, several studies have been conducted on the association with direct post-natal antibiotic exposure, but the results are conflicting. OBJECTIVE: The aim of this study was to investigate pre- and post-natal antibiotic exposure and the subsequent development of eczema, recurrent wheeze and atopic sensitization in children up to the age of 4 years. METHODS: We conducted an aetiologic study in 773 children based on a prospective birth cohort project in which environmental and health information were collected using questionnaires. Antibiotic exposure was assessed as maternal antibiotic intake during pregnancy and during lactation and as medication intake of the child. The chronology of exposures and outcomes was taken into account during the data processing. At the age of 1 and 4 years, a blood sample was taken for the quantification of specific IgE. RESULTS: Prenatal antibiotic exposure was significantly positively associated with eczema, whereas no association was found with recurrent wheeze and atopic sensitization. We found a positive, although statistically not significant, association between antibiotic exposure through breastfeeding and recurrent wheeze. Neither eczema nor atopic sensitization was significantly associated with antibiotic exposure through breastfeeding. Finally, we observed a negative association between the use of antibiotics in the first year of life and eczema and atopic sensitization, and also between antibiotic use after the first year of life and recurrent wheeze, eczema and atopic sensitization. CONCLUSION: Indirect exposure to antibiotics (in utero and during lactation) increases the risk for allergic symptoms in children, while direct exposure to antibiotics appears to be protective. The biological mechanisms underlying these findings still need to be elucidated.

A relativistic type Ibc supernova without a detected gamma-ray burst.

Long duration gamma-ray bursts (GRBs) mark the explosive death of some massive stars and are a rare sub-class of type Ibc supernovae. They are distinguished by the production of an energetic and collimated relativistic outflow powered by a central engine (an accreting black hole or neutron star). Observationally, this outflow is manifested in the pulse of gamma-rays and a long-lived radio afterglow. Until now, central-engine-driven supernovae have been discovered exclusively through their gamma-ray emission, yet it is expected that a larger population goes undetected because of limited satellite sensitivity or beaming of the collimated emission away from our line of sight. In this framework, the recovery of undetected GRBs may be possible through radio searches for type Ibc supernovae with relativistic outflows. Here we report the discovery of luminous radio emission from the seemingly ordinary type Ibc SN 2009bb, which requires a substantial relativistic outflow powered by a central engine. A comparison with our radio survey of type Ibc supernovae reveals that the fraction harbouring central engines is low, about one per cent, measured independently from, but consistent with, the inferred rate of nearby GRBs. Independently, a second mildly relativistic supernova has been reported.

Nasal nitric oxide in cystic fibrosis with and without humming.

BACKGROUND: Nasal nitric oxide (nNO) values are reduced in patients with cystic fibrosis (CF). Humming during nNO measurement increases nNO values in healthy subjects. Nasal NO is reduced in patients with CF, sinus disease or nasal polyps. Humming nNO values have not been reported in CF patients yet. Our aim was to explore humming nNO values in CF patients and assess whether nNO during humming is a better discriminator than silent nNO measurements in this patient group. MATERIALS AND METHODS: In a cross sectional study we measured nNO concentrations in healthy controls (HC) and in CF patients (n = 23 and 31, respectively). The participants held their breath for 10 s while air was passively extracted from one nostril with 700 mL min(-1) for direct NO measurements (NIOX chemiluminescence analyser). Subsequently nNO was measured during humming with the mouth closed for 10 s. RESULTS: Mean nNO in parts per billion (p.p.b.) (SD) during breath hold was 499 (164) and 240 (139), respectively. The median nNO peak (p.p.b., minimum-maximum) during humming was 1500 (425-4100) for HC and 120 (23-500) for CF. There was a highly significant difference between nNO both with and without humming between CF and HC (P < 0.01). The sensitivity and specificity of nNO for detecting CF were better with humming. CONCLUSION: Nasal NO concentrations with and without humming are significantly decreased in CF. Humming nNO is an excellent discriminator between HC and CF and performs better than silent nNO.

Nasal nitric oxide and nasal allergy.

Measurements of nasal nitric oxide (nNO) are attractive because they are completely noninvasive and can easily be performed. The measurements may be useful in the early diagnosis of patients with chronic airway disorders such as Kartager's syndrome and cystic fibrosis. The possible use of nNO measurements in the diagnosis and treatment of allergic rhinitis still needs to be further evaluated because of the variable and also contradicting findings of nNO concentrations in this disease. In this review we will discuss the origin, production and measurement of nNO as well as the effect of allergic rhinitis, nasal allergen challenge and medication on nNO. Subsequently, we examine published data on allergic rhinitis and nNO, and summarize the effect of treatment of rhinitis on nNO. Finally, we discuss the potential future role for nNO in the diagnosis and management of allergic rhinitis.

Nasal NO measurement by direct sampling from the nose during breathhold: Aspiration flow, nasal resistance and reproducibility.

The objective of this study was assessment of the effect of aspiration flow, the nasal cycle, and time on nasal nitric oxide (nNO) concentrations in air sampled from one nostril during breathhold. nNO was measured in 45 healthy subjects (19 males, aged 18-45 years) from one nostril during breathholding. We compared nNO values and time to plateau in both nostrils with 3 aspiration flows (280, 700, 1,200 ml/min) and assessed the short-term and long-term reproducibility. Mean nNO values at flows of 280, 700 and 1,200 ml/min differed significantly (P < 0.01): 854, 474, 380 ppb, respectively. The (median) plateau was reached after 6, 4 and 3 s for the different flows. The within-subject coefficient of variability was always < 5%. We found no difference in nNO between left-, right-, largest or smallest nostril (P > 0.10). nNO values after 6, 24 h and 7 days were not significantly different from baseline (P > 0.10) and showed fair reproducibility. The highest aspiration flow was experienced as unpleasant. nNO can be measured in either nostril and shows no diurnal variation. The measurement is quick, reproducible, feasible and best accepted with an aspiration flow of 700 ml/min during breathhold for 10 s.

Silent and humming nasal NO measurements in adults aged 18-70 years.

BACKGROUND: The concentration of nitric oxide (NO) measured from the nose is much higher than in the lower airways and increases during humming. We assessed nasal NO (nNO) normal values during breath hold and during humming in healthy adults. MATERIALS AND METHODS: Nasal NO concentrations were measured in healthy adults (ages 18-70). They held their breath for 10 s and thereafter hummed as loud as possible with their mouths closed also for 10 s. During breath hold, air was passively extracted from one nostril with 700 mL min(-1). The average NO concentration at the plateau after 7-10 s was recorded and the mean of three consecutive measurements was calculated. During humming, air was extracted with 1200 mL min(-1), the peak NO values were recorded. RESULTS: One hundred healthy adults participated (37 men). The nNO concentrations during breath hold were distributed normally (mean: 455 parts per billion (p.p.b.), SD 147). A random subgroup of 40 out of the 100 subjects (15 men) performed nNO measurement during humming. The median peak NO value was 1019 p.p.b. (SD 561) at the first, and 837 p.p.b. (SD 408) at the second measurement. There was a significant difference between the peak NO values of first and second humming. CONCLUSION: We present normal values for nNO in adults, which can be used to assess the value of nNO in respiratory illnesses. The peak nNO values during humming are variable, and their clinical relevance remains to be shown.

Nasal NO: normal values in children age 6 through to 17 years.

The present study is an assessment of normal values of nasal nitric oxide (nNO) in healthy children. Healthy children aged between 6-17 yrs were recruited from three schools in Rotterdam (The Netherlands). Breath was held for 10 s, while air was extracted from one nostril at 700 mL.min(-1). The mean nNO value at the response plateau after 7-10 s was recorded and the average of three measurements was used. In total, 340 children participated; the male:female ratio was 156:184. Three reliable measurements were available in 85% of the children. The nNO concentrations were distributed normally (mean 449 ppb, SD 115). They were not associated with sex, passive smoking or body mass index. In children aged <12 yrs nNO correlated positively with age, history of adenoidectomy and ambient NO. In children aged > or =12 yrs ambient NO was the only significant modifier. Prediction rules for nNO values in children were formulated. In conclusion, the current study presents normal values for nasal nitric oxide in children, which can be used to assess the value of nasal nitric oxide in respiratory illnesses.

Detection of a radio counterpart to the 27 December 2004 giant flare from SGR 1806-20.

It was established over a decade ago that the remarkable high-energy transients known as soft gamma-ray repeaters (SGRs) are located in our Galaxy and originate from neutron stars with intense (< or = 10(15)G) magnetic fields-so-called 'magnetars'. On 27 December 2004, a giant flare with a fluence exceeding 0.3 erg cm(-2) was detected from SGR 1806-20. Here we report the detection of a fading radio counterpart to this event. We began a monitoring programme from 0.2 to 250 GHz and obtained a high-resolution 21-cm radio spectrum that traces the intervening interstellar neutral hydrogen clouds. Analysis of the spectrum yields the first direct distance measurement of SGR 1806-20: the source is located at a distance greater than 6.4 kpc and we argue that it is nearer than 9.8 kpc. If correct, our distance estimate lowers the total energy of the explosion and relaxes the demands on theoretical models. The energetics and the rapid decay of the radio source are not compatible with the afterglow model that is usually invoked for gamma-ray bursts. Instead, we suggest that the rapidly decaying radio emission arises from the debris ejected during the explosion.

Treatment of hypopharyngeal carcinoma: analysis of nationwide study in the Netherlands over a 10-year period.

OBJECTIVE: To analyse different treatment strategies and treatment results of hypopharyngeal carcinoma in the Netherlands. DESIGN: Retrospective study. SETTING: Eight head and neck centres in the Netherlands. PARTICIPANTS: A total of 893 patients were treated between 1985 and 1994. Patients were mostly treated with radiotherapy alone, combined surgery and radiotherapy and surgery alone. RESULTS: The 5-year survival for the whole group was 26%. The 5-year survival for patients treated with curative intention was 32% and treated with palliative intention was 5%. The 5-year disease-free survival after radiotherapy alone was 37%, after surgery alone 41% and after combined therapy 47%. The role of chemotherapy could not be investigated because of a small number of patients treated with chemotherapy in this period. CONCLUSION: Combined therapy with surgery and radiotherapy has a better survival for patients with a hypopharyngeal carcinoma in comparison with radiotherapy alone. The N-stage is more important for the prognosis than the T-stage.

Increased occurrence of asthma and allergy: critical appraisal of studies using allergic sensitization, bronchial hyper-responsiveness and lung function measurements.

BACKGROUND: Many studies have reported an increase in the occurrence of asthma and respiratory allergies in recent decades, but this increase is mostly based on studies using rather subjective measurements of asthma and allergies, such as questionnaires and doctor's diagnosis. None of the reviews specifically focused on studies using more 'objective' measurements, such as sensitization (specific IgE or skin prick testing (SPT)), bronchial hyper-responsiveness (BHR) or lung function (LF). OBJECTIVE: To review articles studying a time trend of occurrence of these 'more objective' measurements. METHODS: A MEDLINE-search (1966-February 2000) was performed. The following criteria were used: population-based, using IgE, SPT, BHR or LF measurements in the same age-group at least twice, with at least 2 years between and using similar methods. RESULTS: The MEDLINE-search resulted in only 16 articles, performed in 13 populations in seven different countries. Nine articles used the same objective measurements twice in the whole population. Three of these reported a non-significant increase or decrease. The other six articles found a significant increase in at least one objective measurement and of these only three reported a consistent significant increase. CONCLUSIONS: The increase in the occurrence of reported asthma and allergy is supported by only a few articles confirming these results with 'more objective measurements'.

Higher occurrence of asthma-related symptoms in an urban than a suburban area in adults, but not in children.

In young adults, a higher occurrence of asthma-related symptoms was found in an urban than an adjacent suburban area in a survey performed in 1991. The authors now wondered whether such differences could be established in other age groups. The present study (in 1996) included 14,299 subjects, aged 5-75 yrs, of a random sample of the general population in the same two adjacent areas: the centre of Antwerp (Belgium) and its south suburban border. The standardized European Community Respiratory Health Survey (ECRHS) and International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires were used to assess the occurrence of asthma-related symptoms. Higher rates were confirmed in urban compared to suburban Antwerp in adults (20-75 yrs), but no such area differences were found in children (5-8 and 12-15 yrs). Adjustment for a number of recorded risk factors did not seem to affect the area differences in asthma-related symptoms. Comparing the survey results of 1991 and 1996 in 20-44 yr old adults, the findings suggest a slight increase in reported respiratory symptoms in both areas. A higher occurrence of asthma symptoms was observed in the urban than suburban area in adults, but not in children. This might be explained by a progressive effect of long-term exposure to the "urban environment". However, longitudinal studies are necessary to further clarify the factors accounting for these age-related area differences.

Does the use of antibiotics in early childhood increase the risk of asthma and allergic disease?

BACKGROUND: One of the mechanisms evoked to explain the increasing prevalences of asthma and allergy, in particular among children, is the 'Western lifestyle' or 'hygiene' hypothesis. As early childhood infections are assumed to hold a protective effect on the development of asthma and allergies, the use of antibiotics at that sensitive age may lead to an increased risk of asthma and allergy. OBJECTIVE: The aim of this study is to investigate the association between the use of antibiotics in the first year of life and the subsequent development of asthma and allergic disorders. METHODS: In a population-based sample of 7-and-8-year-old children questionnaire and skin prick test data were collected from 1206 and 675 subjects, respectively. Prevalence rates of asthma, allergic disorders and skin test positivity were compared between children with and without early life use of antibiotics, taking into account other possible risk factors including early respiratory infections. The effect of genetic predisposition was investigated by stratified analyses of children with and without parental hay fever. RESULTS: The use of antibiotics during the first year of life was significantly associated with asthma (OR = 1.7, 95% CI 1.0-3.1), hay fever (OR = 2.3, 95% CI 1.3-3.8) and eczema (OR = 1.3, 95% CI 1.0-1.8). No significant relationship was found with skin test positivity (OR = 1.1, 95% CI 0.7-1.7). After stratification for the presence of parental hay fever, children without parental hay fever did not show any significant associations between antibiotics use and asthma or allergy, whereas in children with parental hay fever the use of antibiotics was significantly related with asthma (OR = 2.3, 95% CI 1.1-5.1), hay fever (OR = 2.8, 95% CI 1.5-5.1) and eczema (OR = 1.6, 95% CI 1.0-2.6), and of borderline statistical significance with skin test positivity (OR = 1.6, 95% CI 0.9-3.0). CONCLUSION: Early childhood use of antibiotics is associated with an increased risk of developing asthma and allergic disorders in children who are predisposed to atopic immune responses. These findings support recent immunological understanding of the maturation of the immune system.