Raoul L. Wolf

Fine Mapping and Positional Candidate Studies Identify HLA-G as an Asthma Susceptibility Gene on Chromosome 6p21

Asthma affects nearly 14 million people worldwide and has been steadily increasing in frequency for the past 50 years. Although environmental factors clearly influence the onset, progression, and severity of this disease, family and twin studies indicate that genetic variation also influences susceptibility. Linkage of asthma and related phenotypes to chromosome 6p21 has been reported in seven genome screens, making it the most replicated region of the genome. However, because many genes with individually small effects are likely to contribute to risk, identification of asthma susceptibility loci has been challenging. In this study, we present evidence from four independent samples in support of HLA-G as a novel asthma and bronchial hyperresponsiveness susceptibility gene in the human leukocyte antigen region on chromosome 6p21, and we speculate that this gene might contribute to risk for other inflammatory diseases that show linkage to this region.

A genome-wide search for allergic response (atopy) genes in three ethnic groups: Collaborative Study on the Genetics of Asthma

Atopy is an IgE-mediated condition known to aggregate in families and is a major risk factor for asthma. As part of the Collaborative Study on the Genetics of Asthma (CSGA), a genome-wide scan for atopy, defined by skin sensitivity to one or more common environmental allergens, was conducted in 287 CSGA families (115 African American, 138 Caucasian and 34 Hispanic). Using a nonparametric genetic analysis approach, two regions were observed in the sample of all families that yielded multipoint lod scores >1.5 (chromosome 11q, lod=1.55 between D11S1986 and D11S1998; chromosome 20p between D20S473 and D20S604, lod=1.54). Modeling that included multiple genomic positions simultaneously indicated that four chromosomal regions accounted for the majority of evidence for linkage in the combined families. These four regions are on chromosomes 10p near D10S1412 (lod=0.94), 11q near D11S1986 (lod=1.76), 17q near D17S784 (lod=0.97) and 20p near D20S473 (lod=1.74). In the subset of pedigrees giving positive evidence for linkage on chromosome 11q, the evidence for linkage increased by lod scores greater than one in four other chromosomal regions: 5q (D5S1480, lod=1.65), 8p (D8S1113, lod=1.60), 12p (D12S372, lod=1.54) and 14q (D14S749, lod=1.70). These results suggest that several regions may harbor genes contributing to the risk for atopy and these may interact with one another in a complex manner.

Racial and ethnic disparities in diagnosed and possible undiagnosed asthma among public-school children in Chicago

OBJECTIVES We examined racial and ethnic disparities in the total potential burden of asthma in low-income, racially/ethnically heterogeneous Chicago schools. METHODS We used the Brief Pediatric Asthma Screen Plus (BPAS+) and the Spanish BPAS+, validated, caregiver-completed respiratory questionnaires, to identify asthma and possible asthma among students in 14 racially/ethnically diverse public elementary schools. RESULTS Among 11490 children, we demonstrated a high lifetime prevalence (12.2%) as well as racial and ethnic disparities in diagnosed asthma, but no disparities in prevalences of possible undiagnosed asthma. Possible asthma cases boost the total potential burden of asthma to more than 1 in 3 non-Hispanic Black and Puerto Rican children. CONCLUSIONS There are significant racial and ethnic disparities in diagnosed asthma among inner-city schoolchildren in Chicago. However, possible undiagnosed asthma appears to have similar prevalences across racial/ethnic groups and contributes to a high total potential asthma burden in each group studied. A better understanding of underdiagnosis is needed to address gaps in asthma care and intervention for low-income communities.

Development and validation of a brief pediatric screen for asthma and allergies among children

BACKGROUND Asthma is the most common disease of childhood, but the recognition and detection remain poor, especially among schoolchildren. There has been an increase in the number of instruments available to detect the risk of asthma earlier in children. We have previously validated a simple, self-reported screen, the Brief Pediatric Asthma Screen (BPAS). OBJECTIVE To develop a new screen for asthma and allergies based on the BPAS (BPAS+) with the intent of keeping the screen brief and simple, while including allergy detection. METHODS Questions from the BPAS were extensively revised, and questions regarding allergic rhinitis were added. A panel of parents of asthmatic children reviewed and critiqued the questions. The final BPAS + was distributed in elementary schools, and a cohort of 129 participated in a validation against the gold standard of evaluation by an expert in asthma. RESULTS For asthma the best items were wheeze, persistent cough, night cough, and response to change in air temperature. The simplest scoring, any 1 of the 4 items, yielded the best balance of specificity (73.6%) and sensitivity (73.3%). For allergy, using all six items, having any one or any two of the items had sensitivity of 71.4% and specificity of 77.3%. CONCLUSIONS The BPAS+ provides a rapid and valid method for the detection of potential allergy and asthma in schoolchildren. Sensitivity and specificity are acceptable for both asthma and allergies.

Development and validation of school-based asthma and allergy screening questionnaires in a 4-city study

Background Asthma and allergies are commonly undiagnosed in children. Schools provide settings for potentially accessing almost all children for asthma and allergy screening. Objective To evaluate the feasibility and validity of using a questionnaire-based screening tool to identify undiagnosed asthma and respiratory allergies in children in kindergarten to grade 6. Methods A student questionnaire (SQ) and a parent questionnaire (PQ) were developed, administered in 4 diverse communities, and validated against standardized clinical assessments. Children without diagnosed asthma and representing a range of symptoms participated in a validation study that consisted of independent, standardized, clinical assessments. Sensitivity, specificity, and predictive values for questionnaire items were evaluated against expert consensus designations. Results A total of 190 children (age range, 7–13 years) completed the validation study. Affirmative responses to individual questions from either the SQ or PQ regarding asthma and allergy were modestly to moderately predictive of the clinical assessments (odds ratios, generally 2.5–5.0). When considering a positive asthma screen as affirmative responses to 3 of the best 7 SQ asthma questions, the odds ratio for asthma was 9.3 (95% confidence interval, 4.1–21.1), with 80% sensitivity and 70% specificity. Considering the allergy screen as positive based on affirmative response to either of the 2 SQ allergy questions yielded 81% sensitivity and 42% specificity. Conclusions Either a 9-item SQ or a 10-item PQ can be used in diverse settings to screen for asthma and respiratory allergies. The SQ, obtained by directly screening students, may provide a sensitive approach for detecting children with previously undiagnosed asthma and allergies.

Validation of the Crisis in Family Systems–Revised, a Contemporary Measure of Life Stressors

The objectives of this study were to establish the validity of the Crisis in Family Systems–Revised, a recently developed measure of contemporary life stressors, using the same validation technique as in the original validation and to provide further evidence of construct validity by assessing its relationship to socioeconomic status and residential location. We conducted 124 in-person interviews with parents in three outpatient pediatric asthma clinics affiliated with an academic medical center. The design was cross-sectional and correlational. Total count of life stressors accounted for 19% of the variance in scores on the Center for Epidemiologic Studies–Depression. Respondents using Medicaid and living in the city experienced more objective stressors, but the proportions of stressors rated as negative or positive (Valence), and ongoing (Chronicity) were fairly constant across subsamples, as was the Difficulty rating. Psychologists and health and mental health services researchers are in need of constructs relevant to contemporary society and its issues and tools to measure these constructs. Life stressors appears to be such a construct and the Crisis in Family Systems–Revised a measure with considerable utility.

Soluble inhibitory factor (SIF) in normal human serum

Abstract We have previously noted that dividing T cells release soluble inhibitory factor (SIF) into culture fluids. SIF was distinguished from most other suppressor factors by consisting of two components: a protein and a glycolipid, lipid suppressor substance (LSS). We had noted large quantities of LSS in serum of a patient with a cutaneous lymphoma. This prompted the present study in which SIF was found in normal human serum in a fraction derived by ethanol precipitation. The SIF complex reduced uptake of [ 3 H]thymidine into mixed leukocyte culture (MLC) by 77%. SIF from serum (SIF-serum) resembled SIF in culture fluids (SIF-sup) by chromatography and function at all stages of purification. LSS was extracted from SIF-serum, as measured by an 88% reduction of [ 3 H]thymidine incorporation into phytohemagglutinin-stimulated lymphocytes. The apparent MW of SIF was between 100, 000 and 150, 000. LSS from serum was purified by two-dimensional thin-layer chromatography to apparent homogeneity. The presence of SIF in normal human serum suggests that it may have an in vivo role in immune regulation.

Validation of the Spanish and English versions of the asthma portion of the Brief Pediatric Asthma Screen Plus Among Hispanics

BACKGROUND The health and health care needs of non-English-speaking Hispanic families with children are poorly understood, in part because they are often excluded from research owing to language barriers. Instruments that are valid in English and Spanish are necessary to accurately evaluate the magnitude of asthma prevalence and morbidity among Hispanics. OBJECTIVE To establish the sensitivity and specificity of the English and Spanish versions of the asthma portion of the Brief Pediatric Asthma Screen Plus (BPAS+) in a low-income Hispanic population. METHODS The validation sample consisted of 145 children whose parents completed the BPAS+ in Spanish and 78 whose parents completed it in English. Bilingual clinicians conducted the examinations on which the clinical assessments were based. We compared the BPAS+ results with the clinical assessment findings to determine the sensitivity and specificity of the BPAS + among Hispanics in terms of identifying children who warrant further medical evaluation for asthma. RESULTS The sensitivity and specificity of the asthma portion of the Spanish BPAS+ were 74% and 86%, respectively. The sensitivity and specificity of the asthma portion of the English BPAS+ were 61% and 83%, respectively. CONCLUSIONS The asthma portion of the BPAS+, a valid screen for identifying children who are in need of further evaluation for potentially undiagnosed asthma, is valid for low-income Hispanics in Spanish and English. As the Hispanic population continues to grow, it is imperative that researchers have English and Spanish instruments that are valid for this population.

Characterization of an immune suppressor from transformed human trophoblastic JEG-3 cells☆

Cultured human choriocarcinoma JEG-3 cells secrete an immunosuppressor that inhibits lymphocyte proliferation stimulated by either an antigen or a mitogen. In this study, the immunosuppressive factor was characterized by three methods: ion-exchange and exclusion chromatography, partition in organic solvents, and thin-layer chromatography on silicic acid. This JEG-3 cell factor appeared to be a protein complex of about 150,000-200,000 Da that contained an immunologically active polar lipid. The structural and functional characteristics of JEG-3 cell immunosuppressor are similar if not identical to those of SIF, a suppressor lymphokine derived from T cells. These secretions from transformed trophoblastic cells may correspond to normal placental products or represent a function of malignant cells.

Pharmacokinetic evaluation of olopatadine for the treatment of allergic rhinitis and conjunctivitis.

Introduction: Olopatadine hydrochloride is an antihistamine and mast cell stabilizer available in three forms, including oral, intranasal and ocular preparations. Most of the practical applications focus on the use of olopatadine for the treatment of allergic rhinitis and conjunctivitis via intranasal and ocular routes. Areas covered: This article was formed from a comprehensive literature search with information taken from meta-analyses, systematic reviews, treatment guidelines and clinical studies on children and adults. Articles that have been selected evaluate the use of intranasal and ocular antihistamines and their role in allergic rhinitis and conjunctivitis. Expert opinion: Olopatadine is significantly more effective than placebos in alleviating the symptoms of allergic rhinitis and conjunctivitis. Olopatadine is a viable alternative and addition to the mainstay therapy of these conditions with intranasal steroids and oral antihistamines. The compliance of the patients would be improved if a once-per-day formulation of olopatadine was developed for intranasal application. The future treatments of allergic rhinitis will probably involve a combination of intranasal antihistamine and steroid because clinical trials have demonstrated an improved efficacy without a significant increase in adverse effects.