bluuebunny/crossref_metadata_2025 huggingface dataset:
Asthma in Remission: Can Relapse in Early Adulthood Be Predicted at 18 Years of Age?
Authors: Bollinger Mary Beth
Published: September 2006

Purpose of the Study.

To determine the frequency of asthma relapse in young adults in remission at 18 years over an 8-year follow-up period and to determine possible prognostic indicators of relapse.

Study Population.

A subset of 68 subjects in asthma remission at 18 years of age from of a cohort of 1037 subjects born in New Zealand from 1972 to 1973 followed from birth through the Dunedin Multidisciplinary Health and Development Study.

Methods.

The cohort was enrolled at 3 years old and followed every 2 years until age 15 and again at ages 18, 21, and 26. Subjects were given respiratory questionnaires and lung-function assessment by spirometry. Methacholine testing for bronchial hyperreactivity was performed at 9, 11, 13, 15, and 21 years of age in some. Atopy was assessed by skin tests at ages 13 and 21 years. Remission of asthma at 18 years was defined as no current symptoms with previous reported symptoms at ≥2 previous assessments.

Results.

At 18 years of age, there were 108 subjects with current asthma and 68 subjects with previous asthma in remission. Those in remission at age 18 had a later age of onset of asthma (6.4 ± 4.5 vs 4.7 ± 4 years for current asthma) and had better lung function. Those with current asthma at age 18 were more atopic at age 18, with higher skin-test reactivity for house dust mite and cat. They had higher bronchial hyperreactivity by methacholine at all age points between 9 and 18 than their counterparts in remission. Of the 68 subjects in remission at age 18, 44 remained in remission and 24 relapsed by age 26. Multiple logistic-regression analysis identified dust mite sensitization at age 13 (odds ratio [OR]: 2.63; 95% confidence interval [CI]: 1.23–5.61) and decreased forced expiratory volume in 1 second/forced vital capacity ratio at age 18 (OR: 0.9 per 1% higher ratio; 95% CI: 0.81–0.99). Those with better lung function had lower likelihood of asthma relapse by 16 years of age. Variables such as methacholine reactivity and tobacco smoking were not significant predictors.

Conclusions.

Approximately one third of young adults with a history of asthma in childhood in remission at 18 years of age will relapse by 26 years of age. Most will have mild disease at relapse. There were weak associations with atopy and lower lung function at a young age as predictors of asthma relapse.

Reviewer Comments.

Families often ask if their child will “outgrow” asthma. This study was consistent with other studies in finding that approximately one third of those in remission may have relapse, but the factors found by other groups as potential predictors such as atopy, lower lung function, and tobacco smoking were not as strong.
Safety of Budesonide Inhalation Suspension in Infants Aged Six to Twelve Months With Mild to Moderate Persistent Asthma or Recurrent Wheeze
Authors: James John
Published: September 2006

Purpose of the Study.

To compare the safety of budesonide inhalation suspension (BIS) with placebo.

Study Population.

Infants (aged 6–12 months) with mild-to-moderate persistent asthma or recurrent wheeze.

Methods.

A multicenter, randomized, double-blinded, parallel-group, placebo-controlled study, in which 141 infants received 0.5 mg of BIS (n = 48), 1.0 mg of BIS (n = 44), or placebo (n = 49) once daily for 12 weeks. The primary variable was adrenal function, which was based on cosyntropin-stimulated plasma cortisol levels. Spontaneous adverse events and clinical laboratory findings were monitored.

Results.

Overall, the types and frequencies of adverse events reported during the study were comparable across treatment groups. The response to cosyntropin stimulation was similar across treatment groups, with no significant difference between BIS treatment and placebo.

Conclusions.

The safety profile of BIS was similar to that of placebo, with no suppressive effect on adrenal function in patients 6 to 12 months of age with mild-to-moderate persistent asthma or recurrent wheeze.

Reviewer Comments.

Inhaled corticosteroids remain the preferred choice for the long-term management of persistent asthma in pediatric patients. In addition, because BIS has become available for clinical use, more and more infants and young children with persistent asthma and/or recurrent episodes of wheezing have been managed with this inhaled antiinflammatory medication. In turn, appropriate questions have arisen from caregivers and providers about the overall safety of this therapy in these very young patients. Although the safety and efficacy of nebulized BIS have been confirmed in well-designed investigations in patients 6 months to 8 years of age, controlled clinical studies addressing the safety and efficacy of inhaled corticosteroids exclusively in the infant age range have been lacking. This current investigation provides very useful safety data for BIS in this understudied infant population. The data demonstrate that once-daily administration of BIS, 0.5 or 1.0 mg, was not associated with a decrease in adrenal function, which was based on cosyntropin-stimulated plasma cortisol levels. This information should be very useful to health care providers who prescribe this medication for young infants with mild-to-moderate persistent asthma or recurrent wheeze.
Adult Asthma Severity in Individuals With a History of Childhood Asthma
Authors: Andrews Timothy , Banks James R.
Published: September 2006

Purpose of the Study.

Childhood asthma has a range of outcomes in adulthood. This study sought to identify clinical features and exposures associated with persistence and severity of childhood asthma in adulthood.

Study Population.

Subjects had been previously enrolled in the Childhood Asthma Study, a double-blind, randomized, placebo-controlled trial designed to study the role of immunotherapy as an adjunct treatment. The 121 original study members, aged 5 to 12 years at the time of randomization, had moderate-to-severe asthma and had been followed for at least 1 year before enrollment. Evaluations performed during the original study included daily medication-symptom diaries, home allergen analysis, allergy skin testing, and methacholine challenges. The cohort had varied socioeconomic status, genders, and ethnicities. For this study an attempt was made to enroll all original participants.

Methods.

Eighty-five of the original subjects participated in the adult evaluation, underwent spirometry and inhalant allergy skin testing, and completed questionnaires regarding their interim medical history, asthma symptoms, and medications. Asthma severity was classified by using a modified version of the 1997 National Asthma Education and Prevention Program algorithm. Postbronchodilator spirometry was used for severity categorization. Subjects were categorized in the most severe category for which they qualified.

Results.

Thirteen (15.3%) of these young adults, aged 17 to 30 years, were in remission. Another 19 (22%) had only mild intermittent asthma. There were 12 (14%) with mild persistent asthma, 25 (29%) with moderate persistent asthma, and 16 (19%) with severe persistent disease. Subjects in remission, compared with subjects with mild intermittent or persistent asthma, had lower serum immunoglobulin E in childhood (412 vs 1136 vs 968 ng/mL, respectively) and fewer positive allergy skin tests (7 vs 9 vs 10, respectively, from a panel of 18 allergens). Subjects in remission also had milder childhood asthma, indicated by lower average daily medication usage scores and lower percentage of days on inhaled corticosteroids (13.7% vs 24.7% vs 40.9%). There was no association found between current asthma severity and childhood immunotherapy.

Conclusions.

The prognosis of childhood allergic asthma in adulthood is largely determined early in life. The degree of atopy seems to be a critical determinant of asthma persistence.

Reviewer Comments.

The authors point out that numerous studies of the natural history of asthma have suggested associations between childhood atopy and disease severity with risk of asthma persistence and severity in later childhood and adulthood. It remains to be seen whether there is any sort of intervention at a very early phase in the disease that will more favorably alter the course of asthma. Thus far, there are no compelling candidates.
Self-Organized Patchiness in Asthma as a Prelude to Catastrophic Shifts
Authors: Thatayatikom Akaluck , Liu Andrew H.
Published: September 2006

Purpose of the Study.

To reveal self-organized small airway constriction contributing to large ventilation defects in asthmatics.

Study Population.

Mild and moderate asthmatics.

Methods.

Ventilation defects in asthmatics were studied during methacholine bronchoprovocation by using serial dynamic positron emission tomography with a positron-emitter nitrogen-13 tracer and a single terminal-airway model.

Results.

Heterogeneity of ventilation defects in asthmatics was demonstrated. In this model, constriction of terminal bronchioles was the main feature of bronchoconstriction, contributing to nonuniform ventilation defects. Consequently, on the basis of the mechanical interdependence in expansion between airways and surrounding parenchyma, clusters of constricted terminal bronchioles fed by a common tree branch developed and led to large ventilation defects.

Conclusion.

Clustered groups of self-organized terminal bronchiolar constriction, not large airways obstruction, contribute to large ventilation defects in acute asthma.

Reviewer Comments.

The nature of functional changes of both small and large airways affecting ventilation during acute asthma attacks has been unclear. Previously, MRIs of asthmatic lungs during bronchoprovocation suggested large-airway obstruction as a major cause of large ventilation defects (eg, J Allergy Clin Immunol. 2003;111:1205–1211). In this study, Venegas et al demonstrated the role of clustered terminal bronchiolar constriction resulting in ventilation defects in acute asthma. On the basis of this model, inhaled bronchodilators could be ineffective because the inhaled form might reach only well-ventilated regions and could further impede lung expansion of problematic regions and exacerbate regional ventilation defects. The concept of catastrophic shifts might account for sudden, unexplained, and severe asthma attacks in some patients. Systemic bronchodilators may be needed in some asthmatics to bypass this problem. This line of investigation is further elucidated elsewhere (J Appl Physiol. 2005;99:2388–2397).
Initial High-Dose Nasal Allergen Exposure Prevents Allergic Sensitization to a Neoantigen
Authors: Sharma Hemant , Matsui Elizabeth
Published: September 2006

Purpose of the Study.

Epidemiologic studies have suggested that high-dose allergen exposure may protect against primary allergic sensitization—the formation of immunoglobulin E (IgE) after initial antigen exposure. This study uses a human nasal allergic sensitization model to evaluate the effect of the dose of the antigen on the rate of primary sensitization to a neoantigen, keyhole limpet hemocyanin (KLH).

Study Population.

Fifty-one healthy nonsmoking atopic subjects aged 18 to 55 years. Atopic status was defined by a positive skin-prick test to at least one aeroallergen; the subjects therefore had a propensity to mount an allergic (IgE) response to respiratory antigen exposure.

Methods.

Subjects underwent a 33-day sensitization protocol including initial exposure to 0.1-, 10-, 1000-, or 100 000-μg doses of intranasal KLH as well as later exposure to adjuvant intranasal diesel exhaust particles. At the conclusion of protocol, antigen-specific IgE, IgG, and IgG4 were measured in nasal lavage samples.

Results.

The rates of allergic sensitization, defined as detectable KLH-specific IgE, for the 0.1-, 10-, 1000-, or 100 000-μg dose groups were 0, 100, 57, and 11%, respectively. Furthermore, the mean KLH-specific IgE levels decreased with increasing doses of initial antigen exposure. Antigen-specific IgG and IgG4 were produced by all subjects, with the highest levels observed in the high-dose group.

Conclusions.

Initial high levels of respiratory antigen exposure may prevent primary allergic sensitization through induction of an antigen-specific non-IgE humoral immune response.

Reviewer Comments.

In children at high risk of allergic sensitization, a means of preventing primary sensitization and inducing durable allergic tolerance would be of great value. This study found that initial high-dose exposure to a neoantigen, KLH, results in a humoral immune response with high levels of antigen-specific IgG, including IgG4, and low levels of KLH-specific IgE. Whether these findings apply to other respiratory antigens remains unclear. The mechanism underlying this induction of tolerance remains unclear, and it is also not known whether this immune response represents durable allergic tolerance. Future studies investigating these issues are needed to move toward potential primary prevention therapy for allergic disease.
The Bronchial Lavage of Pediatric Patients With Asthma Contains Infectious Chlamydia
Authors: Perry Tamara T.
Published: September 2006

Purpose of the Study.

To examine the frequency of Chlamydia pneumoniae infections in pediatric patients with asthma.

Study Population.

Seventy pediatric patients undergoing flexible fiber-optic bronchoscopy as a part of their ongoing clinical care.

Methods.

Bronchoaveolar lavage (BAL) fluid and blood were examined for the presence of C pneumoniae by smear examination and culture. The BAL and blood samples were cultured on human or mouse macrophages to determine infectivity. Polymerase chain reaction (PCR) amplification of BAL samples was performed to confirm specificity of the culture technique. Blood was examined for total immunoglobulin E (IgE). Blood samples from 70 matched, nonrespiratory control patients were cultured for Chlamydia.

Results.

Forty-two patients undergoing bronchoscopy had asthma and 28 had various other respiratory diseases. Thirty-eight (54%) BAL samples were positive for Chlamydia by PCR and 22 (31%) samples were positive for Chlamydia by culture. Of the positive BAL samples, 28 (74%) of 38 PCR-positive and 14 (64%) of 22 culture-positive samples were from children with asthma. Culture-positive blood samples were found in 24 (34%) of 70 respiratory patients and 8 (11%) of 70 nonrespiratory controls. In the blood culture–positive respiratory group, 17 (71%) of 24 were from children with asthma. Elevated total serum IgE was associated with BAL culture–positive results, and this relationship was stronger than total IgE and asthma diagnosis.

Conclusions.

Viable C pneumoniae organisms are frequently present in the lung lavage in a cohort of predominately asthmatic pediatric patients.

Reviewer Comments.

Results from this study suggest that infectious C pneumoniae may be common in BAL fluid of children with asthma. Historically, C pneumoniae has been associated with exacerbation and increased incidence of respiratory conditions in adults, but studies to examine similar associations in children have not been performed. This is the first investigation to report viable and infectious C pneumoniae in the BAL fluid of children with asthma. These findings are intriguing and should encourage investigators to examine the clinical implications of Chlamydia infection among pediatric patients with asthma.
Comparative Efficacy and Safety of Low-Dose Fluticasone Propionate and Montelukast in Children With Persistent Asthma
Authors: Duplantier John E.
Published: September 2006

Purpose of the Study.

To evaluate efficacy, safety, health outcomes, and cost-effectiveness of fluticasone propionate (FP) versus montelukast in children with asthma

Study Population.

Children aged 6 to 12 years with persistent asthma.

Methods.

Multicenter, randomized, double-blind, double-dummy, parallel-group study of 342 children with persistent asthma. Children received either FP 50 μg twice daily via Diskus or montelukast 5 mg once daily for 12 weeks. The primary efficacy variable was percent change in morning predose forced expiratory volume in 1 second at the end point.

Results.

Compared with montelukast, children treated with FP experienced a significantly greater increase in mean percent forced expiratory volume in 1 second, mean morning peak expiratory flow rate, and mean evening peak expiratory flow rate. Children treated with FP also experienced significantly greater reductions in total supplemental albuterol use, mean nighttime albuterol use, and mean nighttime symptom scores compared with children treated with montelukast. There were no significant differences between the groups for daytime asthma symptom scores, daytime albuterol use, percent symptom-free days, or adverse events. Parent and physician satisfaction ratings were significantly higher for FP treatment. The daily total asthma-related cost per patient in the FP group was approximately one third of the cost in the montelukast group.

Conclusions.

FP was significantly more effective than montelukast in improving pulmonary function, asthma symptoms, and rescue albuterol use. Both therapies had similar safety profiles.

Reviewer Comments.

Comparative studies in adults and adolescents have previously shown greater efficacy with inhaled corticosteroids versus leukotriene receptor antagonists. This 12-week study reports similar findings for children 6 to 12 years of age with persistent asthma. Based on efficacy, cost, and safety profiles, low-dose inhaled corticosteroids should be considered first-line therapy in this age group.
An Immunoepidemiological Approach to Asthma: Identification of in-Vitro T-Cell Response Patterns Associated With Different Wheezing Phenotypes in Children
Authors: Simons Elinor
Published: September 2006

Purpose of the Study.

To determine if variations in clinical asthma phenotypes are the result of differences in underlying T-cell immune responses to inhalant allergens.

Study Population.

One hundred forty-seven children (aged 8.6–13.5 years) and 25 of their siblings (aged 7.4–17.4 years) were recruited from 194 members of a birth cohort studied prospectively for asthma development.

Methods.

Wheeze and asthma were defined by parental questionnaire. Atopy was defined as at least 1 positive skin-prick test for environmental or food allergens. Increased bronchial hyperreactivity (BHR) was defined as a ≥20% drop in forced expiratory volume in 1 second after inhaled histamine up to 7.8 μmol/L. T-cell responses to allergens and mitogens, blood eosinophils, and immunoglobulin E (IgE) were measured and compared with clinical phenotypes.

Results.

Ninety-five (55.2%) of the children were atopic, sensitized predominantly to house dust mite (42.4%). Asthma was present in 26 (15.1%) children, of whom 22 (85%) were atopic; BHR was present in 62 (35.9%) children, of whom 45 (73%) were atopic. Atopy was associated with T-helper 2 (Th2) cytokine responses (interleukin-4 [IL-4], IL-5, IL-9, IL-13), whereas Th1 responses (IL-10, interferon-γ [IFN-γ], tumor necrosis factor-α [TNF]) occurred in all children. Skin-prick test wheal size was positively associated with house dust mite allergen-induced IL-5 (P < .0001) and IFN-γ (P = .003) and negatively associated with IL-10. Asthma was associated with eosinophilia and elevated house dust mite–specific IL-5, IL-9, IL-13, and IgE. BHR was associated with eosinophilia, elevated allergen-specific IL-5 and IgE, increased total IgE, and a polyclonal cytokine response (IL-5, IL-13, IFN-γ, and TNF-α). In atopics, current asthma or wheeze was associated with house dust mite allergen-specific IL-5 and IL-13; BHR was associated with IL-5 and IgE. In nonatopics, BHR was associated with increased house dust mite allergen-specific and polyclonal IL-10 and polyclonal IFN-γ and TNF-α.

Conclusions.

In atopic and nonatopic children, distinctive immune-response patterns were identified for asthma and BHR. Immunologic Th1 and Th2 hyperresponsiveness was identified as a hallmark of BHR.

Reviewer Comments.

Modification of T-cell responses has become an increasingly important focus in the investigation of treatments for atopic disease. Although this study further highlights the prominence of Th2-driven responses in atopic individuals, the results also demonstrate allergen-specific and polyclonal Th1 responses associated with BHR in atopic and nonatopic children. These findings suggest a nonantagonistic interaction between Th1 and Th2 pathways in the production of asthma symptoms. Further understanding of the associations between T-cell response patterns and clinical wheezing phenotypes in children may lead to future asthma therapies in this population.
Asthma Phenotypes, Risk Factors, and Measures of Severity in a National Sample of US Children
Authors: Gern James E.
Published: September 2006

Purpose of the Study.

To determine if there are differences in risk factors and measures of severity between children with different asthma phenotypes.

Study Population.

The authors reviewed data from children aged 6 to 16 years derived from the Third National Health and Nutrition Examination Survey.

Methods.

The authors used questionnaire and skin-prick–testing data to separate children into the following categories: atopic asthma, nonatopic asthma, resolved asthma, frequent respiratory symptoms with no asthma diagnosis, and normal. Multivariate regression was used to determine if demographic or potential risk factors varied between phenotypes and whether measures of severity varied by phenotype.

Results.

A total of 4.8% of children had atopic asthma, 1.9% had nonatopic asthma, 3.4% had resolved asthma, and 4.3% had frequent respiratory symptoms. Mean BMI was higher among children with nonatopic asthma, whereas prenatal maternal smoking was a risk factor for resolved asthma. Atopic and nonatopic asthma were similar for most measures of asthma severity (eg, medication use and lung function), and relatively few children in either group were receiving inhaled corticosteroids (5%–10%). Patients with resolved asthma had fewer symptoms but lung-function impairment similar to that seen with current asthma, whereas children with frequent respiratory symptoms but no asthma diagnosis had normal lung function.

Conclusions.

The authors conclude that asthma risk factors and measures of severity vary between children with different asthma phenotypes.

Reviewer Comments.

Studies of children and adults have identified several unique phenotypes of asthma that share the feature of chronic and/or recurrent airflow obstruction. Accurate categorization is crucial in efforts to define genetic and environmental risk factors for asthma, and this work uses a very large national database to help establish environmental correlates to asthma subgroups in children. Notably, resolved asthma was linked to prenatal exposure to tobacco smoke and also to persistent impairment in lung function. Because environmental and lifestyle factors are almost certainly behind the rise in asthma prevalence, this line of research is clearly valuable from a public health perspective.
A National Prospective Study on Childhood Celiac Disease in the Netherlands 1993–2000: An Increasing Recognition and a Changing Clinical Picture
Authors: Duplantier John E.
Published: September 2006

Purpose of the Study.

To investigate whether the incidence of diagnosed celiac disease (CD) is increasing in the Netherlands and whether the clinical presentation is changing.

Study Population.

Children between the ages of 0 and 14 years with newly diagnosed cases of CD from 1993–2000.

Methods.

Diagnosis of CD was based on biopsy of the small intestine. The following data were collected: age, gender, weight, height, and aspects of the presenting clinical picture.

Results.

The overall crude incidence rate for CD from 1993–2000 was 0.81 per 1000 live births. There was a significant linear increase of the crude incidence from 1993–2000. During the period of 1993–2000 there was a significant increase in the diagnosis of CD with partial villous atrophy of the small-bowel mucosa and a relative decrease in the diagnosis with subtotal villous atrophy. Fewer children are presenting with abdominal distention, chronic diarrhea, and failure to thrive, and more children are presenting with weight <10th percentile, abdominal pain, and lassitude.

Conclusions.

The increase in newly diagnosed cases of CD seems to represent greater awareness of the disease and the availability of serologic tests. The increase in the number of children with CD diagnosed with small-bowel biopsy specimens showing partial villous atrophy suggests increased recognition of milder cases

Reviewer Comments.

In the United States, CD now seems to affect ∼0.5 to 1.0% of the population (10 times higher than previous estimates). In the past, diagnosis of CD has taken an average of 10 years. Serologic screening (eg, tissue transglutaminase immunoglobulin A antibodies) should be considered for children with symptoms of diarrhea, abdominal cramping, pain, and distention as well as short stature and delayed puberty; individuals with Down syndrome or type 1 diabetes mellitus; and first-degree relatives of patients with biopsy-proven CD. Positive serologic tests should be followed up by small-bowel biopsy. Increased awareness of CD allows earlier diagnosis and institution of a gluten-free diet.
Bacterial Contamination of Spacer Devices Used by Asthmatic Children
Authors: Leo Troy , Leo Harvey L.
Published: September 2006

Purpose of the Study.

To investigate bacterial contamination in spacer devices used by asthmatic children and the device-maintenance procedures practiced by parents.

Study Population.

The study group consisted of 62 consecutive children (aged 2–5 years) attending a clinic. All were enrolled in the study during an acute asthma attack.

Methods.

Spacer devices used by 62 asthmatic children were examined. Swabs taken from the inner surface of the reservoirs and face masks were cultured. Parents were interviewed regarding their spacer-cleaning and -disinfection routines.

Results.

Bacterial contamination was noted in 22 reservoirs (35.5%) and 16 masks (25.8%). Pseudomonas aeruginosa was isolated from 21.0% of the reservoirs and 14.5% of the face masks, Klebsiella pneumoniae from 6.5% and 4.8%, and Staphylococcus aureus from 9.7% and 8.1%, respectively. Only 34 parents (54.8%) reported that they received cleaning and maintenance instructions from the medical staff at initiation of spacer use by their child, and only 38 (61.8%) cleaned the device after each use.

Conclusions.

Bacterial contamination is common in spacer devices. This study demonstrates that contamination rates are significantly lower when parents clean and actually dry (preferably with an air blower) spacer devices after each use. Spacer device maintenance should be emphasized in education programs for managing asthma.

Reviewer Comments.

This study underscores the need for pediatricians and families to be educated about the proper care of spacer devices and the potential risks associated with improper cleaning. In particular, simple cleansing techniques can lessen or eliminate the number of nosocomial infections introduced by poor care of these devices. The benefit of metered-dose inhalers used with spacers and a face mask is high, and it is worthwhile to ensure that patients and health care workers use these devices properly and to their best advantage.
Development of Population-Based Newborn Screening for Severe Combined Immunodeficiency
Authors: Bonilla Francisco A.
Published: September 2006

Purpose of the Study.

To evaluate analysis of T-cell development as a potential population-screening method for severe combined immunodeficiency (SCID).

Study Population.

Twenty-three infants with SCID, 2 patients without SCID, 245 randomly selected infants, and several healthy adults.

Methods.

DNA was extracted from dried blood spots on standard newborn screening (Guthrie) cards. The DNA was subjected to polymerase chain reaction (PCR) to amplify and quantitate the number of T-cell receptor excision circles (TRECs), a marker of T-cell development in the thymus. For comparison, the β-actin gene was also amplified by PCR.

Results.

None of the SCID patients’ blood spots contained detectable TRECs, whereas the infants without SCID had normal TRECs. Healthy adults had normal TRECs, and intentional depletion of T cells led to the disappearance of TRECs in simulated blood spots. Approximately 3% of randomly collected blood spots did not contain measurable TRECs but did contain β-actin.

Conclusions.

Measurement of TRECs by PCR can accurately identify infants with SCID. The relatively high percentage (3%) of screened spots having the SCID profile indicates the need for further refinement of the method before a larger population study.

Reviewer Comments.

Newborn screening for SCID is desirable because of the rapidly fatal nature of this disease and because of the good outcomes that may be obtained with the earliest possible diagnosis. The minimum estimate of the incidence of SCID is >1 per 100 000 births, comparable to other diseases that are already part of newborn screening programs. Almost all patients with SCID lack detectable TRECs. The ability to accurately measure them in dried blood spots represents a tremendous advance toward the possibility of effective newborn screening for this genetically very heterogeneous group of disorders. If the specificity of the analysis can be improved, this may soon be implemented in newborn screening programs.
Long-term Treatment of Atopic Dermatitis With Pimecrolimus Cream 1% in Infants Does Not Interfere With the Development of Protective Antibodies After Vaccination
Authors: Spergel Jonathan M.
Published: September 2006

Purpose of the Study.

To examine if pimecrolimus 1% cream in the treatment of atopic dermatitis would have any effect on vaccinations.

Study Population.

A total of 91 children with mild-to-severe atopic dermatitis (AD), aged 3 to 23 months at enrollment.

Methods.

Children were enrolled in a 1-year double-blind study (76 children received pimecrolimus, and 15 children received placebo). All 91 children were enrolled in a 1-year open-label extension study of pimecrolimus 1% cream. Patients were treated with either pimecrolimus 1% cream or placebo for initial symptoms, and more potent topical corticosteroids were used for flares not prevented by pimecrolimus 1% cream. Patients were vaccinated at normal scheduled times (4 doses of tetanus and diphtheria and 1 or 2 doses of measles and rubella). Response was evaluated at months 18 and 24 of the 2-year period.

Results.

The seropositivity rates of 93.6% for tetanus, 88.6% for diphtheria, 88.5% for measles, and 84.4% for rubella were comparable with those reported in the literature. Seropositivity was not significantly affected by the use of pimecrolimus at the time of vaccinations (±28 days). These seropositivity rates were within the ranges of 87% to 100% for tetanus, 83.3% to 99.3 for diphtheria, 60.5% to 97.1% for measles, and 55.6% to 88.1% for rubella, similar to those reported in age-matched pediatric populations.

Conclusion.

Topical pimecrolimus in the treatment of atopic dermatitis had no effect on the response to routine childhood vaccination.

Reviewer Comments.

Topical pimecrolimus, similar to topical tacrolimus (J Am Acad Dermatol. 2005;53[2 suppl 2]:S206–S213), had no effect on routine childhood vaccination. These topical calcineurin inhibitors did not affect basic B-cell function as measured by postvaccination titers.
Clinical Use of Noninvasive Measurements of Airway Inflammation in Steroid Reduction in Children
Authors: Perry Tamara T.
Published: September 2006

Purpose of the Study.

To examine the clinical utility of noninvasive measures of airway inflammation as predictors for successful inhaled corticosteroid (ICS) dose reduction in children with asthma.

Study Population.

Forty children (aged 6–17 years) with stable asthma on a constant ICS dose and eligible for steroid dose reduction.

Methods.

Children were followed prospectively every 8 weeks with noninvasive measures of airway inflammation including exhaled nitric oxide (eNO), sputum induction with bronchial hyperreactivity testing, and exhaled breath condensate. Physicians who were unaware of the results of inflammatory measures made reductions in the steroid dose on the basis of clinical assessment and spirometry. Multiple logistic-regression models were used to determine the usefulness of noninvasive inflammatory markers in predicting successful steroid reduction.

Results.

Seventy-five percent of patients tolerated a reduction in steroid dose for at least 2 months; however, 15 (38%) of the 40 patients’ conditions subsequently failed ICS dose reduction and experienced an asthma exacerbation. All children with absence of sputum eosinophils successfully tolerated dose reduction. Increased eNO ≥22 ppb (odds ratio: 6.3; 95% confidence interval: 3.75–10.58) and increased sputum eosinophils ≥3% (odds ratio: 1.38; 95% confidence interval: 1.06–1.81) were significant predictors of failed ICS dose reduction.

Conclusions.

Noninvasive measures of airway inflammation may be useful tools in optimizing treatment of children with asthma.

Reviewer Comments.

These findings suggest that noninvasive measures of airway inflammation are potential adjunctive tools that can be used in pediatric patients who appear clinically stable. However, their clinical usefulness may be limited by several factors. Sputum induction was not successfully performed in 25% of the children, and some measures including bronchial hyperreactivity and breath condensate did not prove to be useful predictors in this study. In addition, criteria for predicting failure were met in 6 (21%) of 28 and 19 (39%) of 49 occasions for sputum eosinophil and eNO cutoffs, respectively, when the child was successfully weaned on the basis of clinical judgment. Conversely, use of noninvasive markers would have prevented an attempt to wean steroids on >70% of occasions when patients subsequently experienced an exacerbation. Inflammatory markers as sole predictors of success or failure will likely result in both significant undertreatment and overtreatment with ICSs. Treatment algorithms that include noninvasive airway inflammatory markers in conjunction with clinical markers are likely the best approach to optimize therapy in children who appear clinically stable.
Hypoxia-inducible factor-1 in human breast and prostate cancer
Authors: Kimbro K S , Simons J W
Published: September 2006

The tumor microenvironment is best characterized as a fluctuation of hypoxia and nutrient deprivation, which leads to epigenetic and genetic adaptation of clones and increased invasiveness and metastasis. In turn, these hypoxic adaptations make the tumors more difficult to treat and confer increased resistance to current therapies. Part of this adaptation is the regulation of gene products in response to hypoxia. Many of these hypoxia-regulated genes are mediated by the hypoxia-inducible factor 1 (HIF-1) complex, which is composed of a heterodimer pair of HIF-1α and HIF-1β. This heterodimer binds to the promoter of hypoxia-responsive genes, while interacting with other transcription factors, such as p300, signal and transducer of transcription 3, and Redox effector factor 1/apurinic/apyrimidinic endonuclease. HIF-1α levels itself can be regulated by hypoxia transcriptionally and post-translationally through ubiquitination; but the magnitude of the response is modulated by several other pathways, including free radicals that affect crosstalk with HIF-1α/HIF-1β transcriptional activities. HIF-1α has emerged as an important transcription factor in breast cancer and prostate cancer biology, and is expressed in the early stages of mammary and prostate carcinogenesis. Its expression is correlated with diagnostic and prognostic indicators for early relapse and metastatic disease, thus making HIF-1α a potential prognostic biomarker in proteomic assessments of breast and prostate cancers. The importance of HIF-1α in tumor progression makes it a logical target for chemoprevention strategies in patients at higher genetic risk of breast and prostate cancer with Cox 2 inhibitors or 2-methoxyestradiol, as well as a target for new approaches to inhibiting angiogenesis. The crosstalk between estrogen signaling pathways and HIF-1α is still not fully defined in breast cancer, but downstream estrogen receptor signaling may be a candidate for estrogen modulation of HIF-1α levels. In prostate cancer, androgens upregulate HIF-1α through androgen-regulated autocrine receptor tyrosine kinase receptor signaling. This review will put into perspective the role of HIF-1α in endocrine oncology and present new data on HIF-1α signaling and the potential for targeted therapies, including combinatory hormonal therapies.
Combinatorial androgen receptor targeted therapy for prostate cancer
Authors: Singh P , Uzgare A , Litvinov I , Denmeade S R , Isaacs J T
Published: September 2006

Prostatic carcinogenesis is associated with changes in the androgen receptor (AR) axis converting it from a paracrine dependence upon stromal signaling to an autocrine-initiated signaling for proliferation and survival of prostatic cancer cells. This malignant conversion is due to gain of function changes in which the AR activates novel genomic (i.e. transcriptional) and non-genomic signaling pathways, which are not present in normal prostate epithelial cells. During further progression, additional molecular changes occur which allow these unique malignancy-dependent AR signaling pathways to be activated even in the low androgen ligand environment present following androgen ablation therapy. These signaling pathways are the result of partnering the AR with a series of other genomic (e.g. transcriptional co-activators) or non-genomic (e.g. steroid receptor co-activator (Src) kinase) signaling molecules. Thus, a combinatorial androgen receptor targeted therapy (termed CART therapy) inhibiting several points in the AR signaling cascade is needed to prevent the approximately 30,000 US males per year dying subsequent to failure of standard androgen ablation therapy. To develop such CART therapy, a series of agents targeted at specific points in the AR cascade should be used in combination with standard androgen ablative therapy to define the fewest number of agents needed to produce the maximal therapeutic anti-prostate cancer effect. As an initial approach for developing such CART therapy, a variety of new agents could be combined with luteinizing hormone-releasing hormone analogs. These include: (1) 5α-reductase inhibitors to inhibit the conversion of testosterone to the more potent androgen, dihydrotestosterone; (2) geldanamycin analogs to downregulate AR protein in prostate cancer cells, (3) ‘bulky’ steroid analogs, which can bind to AR and prevent its partnering with other co-activators/signaling molecules, and (4) small molecule kinase inhibitors to inhibit MEK, which is activated as part of the malignant AR signaling cascade.
Pure oestrogen antagonists for the treatment of advanced breast cancer
Authors: Howell Anthony
Published: September 2006

For more than 30 years, tamoxifen has been the drug of choice in treating patients with oestrogen receptor (ER)-positive breast tumours. However, research has endeavoured to develop agents that match and improve the clinical efficacy of tamoxifen, but lack its partial agonist effects. The first ‘pure’ oestrogen antagonist was developed in 1987; from this, an even more potent derivative was developed for clinical use, known as fulvestrant (ICI 182,780, ‘Faslodex’). Mechanistic studies have shown that fulvestrant possesses high ER-binding affinity and has multiple effects on ER signalling: it blocks dimerisation and nuclear localisation of the ER, reduces cellular levels of ER and blocks ER-mediated gene transcription. Unlike anti-oestrogens chemically related to tamoxifen, fulvestrant also helps circumvent resistance to tamoxifen. There are extensive data to support the lack of partial agonist effects of fulvestrant and, importantly, its lack of cross-resistance with tamoxifen. In phase III studies in patients with locally advanced or metastatic breast cancer, fulvestrant was at least as effective as anastrozole in patients with tamoxifen-resistant tumours, was effective in the first-line setting and was also well tolerated. These data are supported by experience from the compassionate use of fulvestrant in more heavily pretreated patients. Further studies are now underway to determine the best strategy for sequencing oestrogen endocrine therapies and to optimise dosing regimens offulvestrant. At present, and for the foreseeable future, fulvestrant is the only oestrogen antagonist with no agonistic effects licensed for the treatment of advanced breast cancer in postmenopausal women. Other similar oestrogen antagonists are undergoing research and development, with a few currently being evaluated in phase II trials.
Progesterone metabolites in breast cancer
Authors: Wiebe John P
Published: September 2006

In the 70 years since progesterone (P) was identified in corpus luteum extracts, its metabolism has been examined extensively in many tissues and cell lines from numerous species. In addition to the reproductive tissues and adrenals, every other tissue that has been investigated appears to have one or more P-metabolizing enzyme, each of which is specific for a particular site on the P molecule. In the past, the actions of the P metabolizing enzymes generally have been equated to a means of reducing the P concentration in the tissue microenvironment, and the products have been dismissed as inactive waste metabolites. In human breast tissues and cell lines, the following P-metabolizing enzymes have been identified: 5α-reductase, 3α-hydroxysteroid oxidoreductase (3α-HSO), 3β-HSO, 20α-HSO, and 6α-hydroxylase. Rather than providing diverse pathways for inactivating and controlling the concentration of P in breast tissue microenvironments, it is proposed that the enzymes act directly on P to produce two types of autocrines/paracrines with opposing regulatory roles in breast cancer. Evidence is reviewed which shows that P is directly converted to the 4-pregnenes, 3α-hydroxy-4-pregnen-20-one (3α-dihydroprogesterone; 3αHP) and 20α-dihydroprogesterone (20αHP), by the actions of 3α-HSO and 20α-HSO respectively and to the 5α-pregnane, 5α-pregnane-3,20-dione(5α-dihydroprogesterone; 5αP), by the irreversible action of 5α-reductase. In vitro studies on a number of breast cell lines indicate that 3αHP promotes normalcy by downregulating cell proliferation and detachment, whereas 5αP promotes mitogenesis and metastasis by stimulating cell proliferation and detachment. The hormones bind to novel, separate, and specific plasma membrane-based receptors and influence opposing actions on mitosis, apoptosis, and cytoskeletal and adhesion plaque molecules via cell signaling pathways. In normal tissue, the ratio of 4-pregnenes:5α-pregnanes is high because of high P 3α- and 20α-HSO activities/expression and low P 5α-reductase activity/expression. In breast tumor tissue and tumorigenic cell lines, the ratio is reversed in favor of the 5α-pregnanes because of altered P-metabolizing enzyme activities/expression. The evidence suggests that the promotion of breast cancer is related to changes in in situ concentrations of cancer-inhibiting and -promoting P metabolites. Current estrogen-based theories and therapies apply to only a fraction of all breast cancers; the majority (about two-thirds) of breast cancer cases are estrogen-insensitive and have lacked endocrine explanations. As the P metabolites, 5αP and 3αHP, have been shown to act with equal efficacy on all breast cell lines tested, regardless of their tumorigenicity, estrogen sensitivity, and estrogen receptor/progesterone receptor status, it is proposed that they offer a new hormonal basis for all forms of breast cancer. New diagnostic and therapeutic possibilities for breast cancer progression, control, regression, and prevention are suggested.
Mechanisms of action of novel agents for prostate cancer chemoprevention
Authors: Singh Rana P , Agarwal Rajesh
Published: September 2006

Despite advances in the understanding of prostate cancer (PCa) growth and development, it is still the leading incidence of cases and the second leading cause of mortality due to cancer in men. The problem of early diagnosis compounded with the emergence of androgen independence during commonly used anti-androgen therapy of PCa, have been discouraging for optimal therapeutic response. Recently, many chemopreventive agents, including silibinin, inositol hexaphosphate, decursin, apigenin, acacetin, grape seed extract, curcumin, and epigallocatechin-3 gallate have been identified in laboratory studies, which could be useful in the management of PCa. In vivo pre-clinical studies have indicated chemopreventive effect of many such agents in PCa xenograft and transgenic mouse models. The molecular targets of these agents include cell signaling, cell-cycle regulators, and survival/apoptotic molecules, which are implicated in uncontrolled PCa growth and progression. Furthermore, angiogenic and metastatic targets, including vascular endothelial growth factor, hypoxia-inducing factor-1α, matrix metalloproteinase, and urokinase-type plasminogen activator are also modulated by many chemopreventive agents to suppress the growth and invasive potential of PCa. This review focuses on novel PCa chemopreventive observations in laboratory studies, which could provide the rationale for the prospective use of chemopreventive agents in translational studies.
Pituitary tumours: findings from whole genome analyses
Authors: Farrell W E
Published: September 2006

Pituitary tumours are common intracranial neoplasms that cause significant morbidity through mass effects and/or the inappropriate secretion of pituitary hormones. Despite a considerable literature detailing potential pathogenic changes in these tumours, their aetiology remains largely unresolved. Recent studies have employed genome-wide profiling towards the identification of novel genes and pathways that are inappropriately expressed or regulated in this tumour type. The techniques employed vary in their complexity and interpretation; however, many of the findings from these types of studies have identified novel genes with potential and, in some cases, proven roles in pituitary tumorigenesis. These studies include comparative genomic hybridization, whole genome-wide allelotyping and methodologies for identification of novel genes associated with epigenetic silencing. In addition, differential display methodologies have been instrumental in the identification of transcripts inappropriately expressed including, pituitary tumour transforming gene, growth arrest and DNA damage-inducible protein (GADD)45γ and a maternal expressed gene 3 isoform, which in some cases have proven roles in pituitary tumorigenesis. Although few studies of whole genome transcript analysis, as determined by microarray or gene-chip technologies, are reported, these studies of human pituitary, in some cases combined with proteomics, are yielding useful data. In addition, these types of investigation have been applied to several animal models of pituitary tumorigenesis, and in these cases novel genes are highlighted as showing significant change. The identification of the initiating events responsible for the transformation of a normal pituitary cell into one with unrestrained proliferative capacity has so far eluded us. No doubt, these new technologies allowing an essentially unbiased genome-wide analysis, perhaps in combination with animal models that display a preceding hyperplasia, will allow us to identify genes critical to tumour evolution and progression.