bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic susceptibility to asthma and atopy among Chinese in Singapore – linkage to markers on chromosome 5q31–33
Authors: Shek L. P‐C. , Tay A. H. , Chew F. T. , Goh D. L. M. , Lee B. W.
Published: March 2003

Background: Asthma and atopy are complex genetic traits, influenced by the interaction of multiple genes and environmental factors. Linkage of these traits to chromosome 5q31–33 has been shown in other populations, but has not been well studied in the Chinese. We studied linkage between asthma and atopy with markers on chromosome 5q31–33 in the Singapore Chinese. This region contains many candidate genes, including the cytokine gene cluster.

Methods: We recruited 88 Chinese families with at least two affected offspring, totaling 373 subjects, with 125 and 119 sib‐pairs for atopy and asthma, respectively. All individuals were genotyped with 19 polymorphic microsatellite markers spanning a distance of 41 cM along chromosome 5q31–33. Affected sib‐pair and multipoint linkage analysis was performed.

Results: There was evidence for linkage of the asthma and atopy phenotypes with three markers, D5S2110, D5S2011, and D5S412 (P values of 0.001 to 0.00001). Multipoint analysis further substantiated this (nonparametric linkage scores of 1.8–2.9). These findings suggest that susceptibility genes for asthma and atopy are found in this region in the Chinese.

Conclusions: This study has shown linkage of atopy and asthma to chromosome 5q31–33 in a heterogeneous Chinese population. These findings further substantiate the notion that chromosome 5q31–33 contains “universally” important susceptibility genes for these traits.
No linkage and association of atopy to chromosome 16 including the interleukin‐4 receptor gene
Authors: Haagerup A. , Bjerke T. , Schiøtz P. O. , Dahl R. , Binderup H. G. , Kruse T. A.
Published: March 2003

Background: Several susceptibility genes for atopy have been suggested in recent years. Few have been investigated as intensively as the interleukin‐4‐receptor α (IL4Rα) gene on chromosome 16. The results remain in dispute. Therefore, in a robust design, we tested for association of type I allergy to the IL4R variations I50V and Q576R, and investigated chromosome 16 for atopy candidate regions in general.

Methods: We identified 100 Danish allergy sib‐pair families. Five conservative phenotypes for type I allergy were defined and evaluated. The IL4R variations were genotyped in trios and evaluated by the transmission disequilibrium test (TDT). Multipoint linkage analysis and exclusion mapping were conducted with sib‐pairs analyzed for 17 microsatellite markers.

Results: No evidence for association or linkage to the IL4R polymorphisms was found (P values: 0.12–0.90). Linkage analysis did not support linkage of any of the phenotypes to chromosome 16. Major parts of chromosome 16 were excluded as candidate regions harboring oligogenes for type I allergy.

Conclusions: We found chromosome 16 unlikely to harbor strong candidate genes for type I allergy. The role of the IL4Rα gene in the inheritance of atopy was insignificant in the Danish population. The use of conservative allergy phenotypes in the search for genes predisposing to atopic disease was discussed.
Effects of budesonide and fluticasone propionate in a placebo‐controlled study on symptoms and quality of life in seasonal allergic rhinitis
Authors: Ciprandi G. , Canonica W. G. , Grosclaude M. , Ostinelli J. , Brazzola G. G. , Bousquet J.
Published: March 2003

Background: Intranasal glucocorticosteroids are effective in seasonal allergic rhinitis. This study compared the efficacy of budesonide (Rhinocort ®Turbuhaler®) and fluticasone propionate (Flixonase®) in this respect.

Methods: Patients (n = 280) were randomized to receive budesonide, 140 µg (delivered dose) once daily, fluticasone, 200 µg once daily, or matching placebos for 5 weeks. The primary efficacy variable was the change in combined nasal symptom (nasal blockage, runny nose, sneezing) scores. Quality of life was measured in 121 patients by means of the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and the Short‐form Health Survey (SF‐36).

Results: Both steroids significantly reduced combined nasal symptoms, compared with placebo. There was no significant difference between the two treatments. Substantial or total symptom control was achieved in 89.9% of the budesonide‐treated patients, compared with 88.7% with fluticasone and 42.7% with placebo. Four of the five domains of the RQLQ were significantly improved with budesonide, whereas with fluticasone only two domains were improved. Budesonide significantly improved scores in five out of eight domains of the SF‐36, whereas no domains were improved with fluticasone.

Conclusion: There was no significant difference in efficacy between budesonide and fluticasone in this study. However, greater improvements in quality of life were seen with budesonide than with fluticasone.
Decreased apoptosis and distinct profile of infiltrating cells in the nasal polyps of patients with aspirin hypersensitivity
Authors: Kowalski M. L. , Grzegorczyk J. , Pawliczak R. , Kornatowski T. , Wagrowska‐Danilewicz M. , Danilewicz M.
Published: March 2003

Background:  Patients with aspirin‐hypersensitive rhinosinusitis/asthma suffer from a severe form of hyperplastic rhinosinusitis with recurrent polyposis. We aimed to assess the presence of apoptotic cells in nasal polyps from aspirin‐hypersensitive (AH) and aspirin‐tolerant (AT) patients with rhinosinusitis as related to the characteristics of local inflammation.

Methods: Nasal polyps obtained from 16 AH patients and 36 AT patients (17 atopic and 19 nonatopic) were stained for eosinophils and metachromatic cells, and in parallel immunocytochemistry was performed to detect CD45RO+, HLA‐DR+, CD8+ and CD68+ positive cells. Apoptotic cells were detected by a nick‐end labelling technique, TUNEL.

Results:  The density of apoptotic cells in AH polyps (5.5 + 1.5 cells/mm2) was significantly lower as compared to both atopic (18.7 + 3.8 cells/mm2; P < 0.02;) and nonatopic (21.3 + 5.2 cells/mm2; P < 0.01) AT polyps. The number of eosinophils, mast cells, and CD45RO+ cells were significantly increased in AH compared to AT polyps (P < 0.001), and the density of HLA‐DR+ cells in AH patients was higher than in nonatopic (P < 0.02), but not in atopic AT patients. While in AH patients the duration of rhinosinusitis correlated inversely with the number of apoptotic cells (r = − 0.67; P < 0.04), in contrast, in AT atopic patients the duration of rhinosinusitis showed positive correlation with apoptosis (r = 0.89; P < 0.003).

Conclusions:  We conclude, that decreased apoptosis of inflammatory cells in nasal polyps from ASA‐hypersensitive patients, reflects a distinct mechanisms of local inflammation and may be related to persistence and severity of the disease in these patients.
Prevalence of sensitization to the predatory mite Amblyseius cucumeris as a new occupational allergen in horticulture
Authors: Giséle C. M. , Groenewoud M. D. , De G raaf in ′t Veld C. , Van Oorschot–van Nes A. J. , De J ong N. W. , Vermeulen A. M. , Van Toorenenbergen A. W. , Burdorf A. , De G root H. , Van Wijk R. G.
Published: March 2003

Background: Protection against thrips, a common pest in bell pepper horticulture is effectively possible without pesticides by using the commercially available predatory mite Amblyzeius cucumeris (Ac). The prevalence of sensitization to Ac among exposed greenhouse employees and its clinical relevance was studied.

Methods: Four hundred and seventytwo employees were asked to fill in a questionnaire and were tested on location. Next to RAST, skin prick tests (SPTs) were performed with common inhalant allergens, the storage mite Tyrophagus putrescentiae (Tp) which serves as a temporary food source during the cultivation process and Ac. Furthermore, nasal challenge tests with Ac were carried out in 23 sensitized employees.

Results: SPTs positive to Ac were found in 109 employees (23%). Work‐related symptoms were reported by 76.1%. Sensitization to Tp was found in 62 employees of whom 48 were also sensitized to Ac. Immunoglobulin (Ig)E‐mediated allergy to inhalant allergens appeared to be an important risk factor for sensitization to Ac. Employees with rhinitis symptoms showed a significantly higher response to all Ac doses during the nasal challenge test compared with employees without rhinitis symptoms.

Conclusions: The predatory mite Ac is a new occupational allergen in horticulture which can cause an IgE‐mediated allergy in exposed employees. It is biologically active on the mucous membranes of the nose and therefore clinically relevant for the development of work‐related symptoms.
Incidence of peripheral blood eosinophilia and the threshold eosinophile count for indicating hypereosinophilia‐associated diseases
Authors: Kobayashi S. , Inokuma S. , Setoguchi K. , Kono H. , Abe K.
Published: March 2003

Background: A definite threshold of the peripheral blood eosinophile count that indicates the presence of hypereosinophilia‐associated diseases has not yet been determined.

Methods: The threshold eosinophile count at which cases of hypereosinophilia‐associated diseases (n = 25) can be differentiated from those of bronchial asthma (n = 101) was determined. Then, the incidences of eosinophile counts greater than 1.0 × 109/l or the threshold level, were studied by analysis of 43 805 samples sent to the laboratory, and the diseases associated with the increased counts were determined.

Results: The eosinophile count in cases of hypereosinophilia‐associated diseases and in those of bronchial asthma were 10.967 ± 1.680 × 109/l and 0.574 ± 0.045 × 109/l, respectively (P < 0.001); the threshold was 2.052 × 109/l. The percentages of samples with an eosinophile count of more than 1.0 × 109/l and 2.052 × 109/l were 0.6% and 0.1%, respectively; the latter comprised of 41 samples from 24 patients including eight with hypereosinophilia‐associated diseases. The patients with hypereosinophilia‐associated diseases had a significantly higher count, and a higher incidence of counts of more than 2.052 × 109/l, than others, including patients with malignancies and symptoms conventionally referred as “atopic diseases”.

Conclusion: Hypereosinophilia‐associated diseases are associated with a very high eosinophile count of more than 2.052 × 109/l, which was observed rarely.
Incidence and host determinants of work‐related rhinoconjunctivitis in apprentice pastry‐makers
Authors: Gautrin D. , Ghezzo H. , Infante‐Rivard C. , Malo J.‐L.
Published: March 2003

Background: The authors recently assessed the incidence and determinants of immunologic sensitization to flour in apprentice pastry‐makers. The aim of this work was to determine the incidence of work‐related rhinoconjunctivitis (RC) symptoms and their determinants.

Methods: For this 188/230 entrants (81.7%) were evaluated before starting exposure to flour, and again 10.8 and 16.8 months after. Questionnaires and skin prick testing to common and work‐related allergens were administered at each visit. Bronchial responsiveness to methacholine was assessed at baseline in all subjects and in a subgroup at follow‐up.

Results: Thirty subjects (16.1%) reported new work‐related RC symptoms (13.1 per 100 person–years); in three subjects (1.6%), these were accompanied by incident skin prick test reactivity to flour‐derived allergens. Skin prick test reactivity to grass pollens (OR = 3.0, 95% CI, 1.3–6.7) and to pets (OR = 2.5, 95% CI, 1.1–5.9), persistent rhinitis (OR = 3.1, 95% CI, 1.1–8.4), seasonal RC (OR = 2.5, 95% CI, 1.1–5.5), RC on contact with pets (OR = 2.3, 95% CI, 1.03–5.0) and skin prick test reactivity to wheat flour (OR = 10.5, 95% CI, 2.3–46.8), assessed at baseline, were significantly associated with the incidence of work‐related RC symptoms. Multivariate logistic regression analysis yielded significant OR of skin prick test reactivity to wheat flour at baseline (OR = 7.1, 95% CI, 1.7–35.1) and persistent rhinitis (OR = 3.9, 95% CI, 1.01–9.6) for the incidence of work‐related RC symptoms. Increased bronchial hyperresponsiveness at follow‐up was more frequent, although not significantly, in subjects positive to skin prick test to flour on entry and reporting new work‐related symptoms (3/5), than in other subjects (4/17).

Conclusions: The incidence of work‐related RC symptoms among apprentice pastry‐makers was high (16.1% 30/186), while a minority (3/30) also developed skin prick test reactivity to flour. Skin prick test reactivity to wheat flour and persistent allergic rhinitis on starting exposure to flour are significant determinants for the development of work‐related RC symptoms.
The unfavorable effects of concomitant asthma and sleeplessness due to the atopic eczema/dermatitis syndrome (AEDS) on quality of life in subjects allergic to house‐dust mites
Authors: Terreehorst I. , Duivenvoorden H. J. , Tempels‐Pavlica Z. , Oosting A. J. , De Monchy J. G. R. , Bruijnzeel‐Koomen C.A. F. M. , Post M. W. M. , Gerth van Wijk R.
Published: March 2003

Background: Allergic rhinitis, asthma or the atopic eczema/dermatitis syndrome (AEDS) may independently impair quality of life in patients. However, although many allergic patients may suffer from more than one disorder, the effect of concomitant disease — in particular, the impact of AEDS — is largely unknown. As part of a large multicenter clinical trial on the efficacy of mattress casings in house‐dust mite (HDM) allergy, generic quality of life in a mixed population of 224 subjects with rhinitis (n = 198) and/or asthma (n = 111) and/or AEDS (n = 64) was studied. The study aimed to estimate quality of life impairment in these atopic patients and to address the questionissue of whether one atopic disorder goes beyond other existing allergic diseases, thereby causing further impairment to quality of life.

Methods: Generic quality of life was assessed by SF‐36. Quality of life in the atopic group was compared with a Dutch norm population. Multiple linear regression was used to determine the effects of disease (i.e. the presence of allergic rhinitis, asthma or AEDS) or disease severity, as assessed by visual analog scores (VAS) for asthma, rhinitis, VAS sleeplessness and VAS itching being considered as major symptoms in AEDS on SF‐36 domains.

Results: Compared to the norm group, atopic patients were impaired in: physical functioning; role physical functioning; general health; vitality; and social functioning. The diagnosis of asthma was negatively associated with the SF‐36 subscales for physical functioning (P = 0.02), and general health (P < 0.01). In line with these findings, asthma severity (VAS asthma) was negatively associated with physical functioning (P < 0.01), role physical functioning (P < 0.01), general health (P < 0.0.1), social functioning (P = 0.01), emotional functioning (P = 0.01), and vitality (P = 0.01). VAS sleeplessness had significant negative effect on role physical functioning (P < 0.01), bodily pain (P < 0.01), General health (P = 0.01), mental health (P < 0.01), social functioning (P < 0.01), and vitality (P < 0.01). In contrast, neither the diagnosis of allergic rhinitis or AEDS, nor VAS itching as an outcome parameter of AEDS, exerted additional effects on the SF‐36 domains.

Conclusions: Patients with atopic disease based on HDM allergy may have impaired quality of life. The majority of these patients have allergic rhinitis. The (co)existence of asthma, expressed in terms of diagnostic criteria or symptom severity, or the presence of sleep disorders as a consequence of AEDS, may further impair quality of life.
The association between tumor necrosis factor, HLA‐DR alleles, and IgE‐mediated asthma in Taiwanese adolescents
Authors: Lin Ying‐Chu , Lu Cheng‐Chan , Su Huey‐Jen , Shen Chen‐Yang , Lei Huan‐Yao , Guo Yueliang Leon
Published: March 2003

Background: Human leukocyte antigen (HLA) DR genes and the tumor necrosis factor (TNF) gene locus are associated with asthma and IgE production. TNFα‐308G/A frequencies between Japanese and Caucasians in the UK have been found to be different. The roles of HLA‐DRB1 and TNF genotypes are unknown in Taiwanese adolescents with IgE‐mediated asthma (I‐asthma).

Methods: From the population of a 1996 nation‐wide survey, we recruited a random sample for a physical examination, determination of total serum IgE (sIgE), dust‐mite‐specific IgE, and HLA‐DRB1, TNFα‐308, and LTαNcoI polymorphisms by polymerase chain reaction.

Results: A total of 80 I‐asthmatics and 69 non‐asthmatics completed the study. We suggested that I‐asthmatics had a higher frequency of the DR13 gene (OR = 8.6, 95% CI = [1.6–161]). The DR13 gene was associated with high sIgE and high dust‐mite‐specific IgE, especially Dermatophagoides farinae. No TNF haplotype or genotype was associated with I‐asthma. The DR13 gene was linked to the LTαNcoI*1 allele. When sIgE was adjusted by multiple logistic regression, the risk of I‐asthma was much higher for the DR13(+)/LTαNcoI*1 haplotype (OR = 25.6, 95% CI = [2.2–1378]) than for the others.

Conclusions: In Taiwanese children sensitized to Der f, the DR13(+)/LTαNcoI*1 haplotype was associated with a much higher risk of having clinical asthma than any other DR13/LTαNcoI haplotype.
Farm residence and exposures and the risk of allergic diseases in New Zealand children
Authors: Wickens K. , Lane J.M. , Fitzharris P. , Siebers R. , Riley G. , Douwes J. , Smith T. , Crane J.
Published: March 2003

Background:Studies in Europe have reported a reduced prevalence of allergy in farmers' children. We aimed to determine if there is a similar reduction in allergy among New Zealand farm children.

Methods:Two hundred and ninety‐three children participated (60%) aged 7–10 years, from selected schools in small towns and the surrounding rural area . Skin prick tests (SPT) to eight common allergens were performed. Parents completed questionnaires about allergic and infectious diseases, place of residence, exposure to animals, and diet, and they provided dust from the living‐room floor. Endotoxin was measured using anLimulusamoebocyte lysate (LAL) assay and Der p 1 using enzyme‐linked immunoassay (ELISA).

Results:Current farm abode was found to increase the risk of having symptoms associated with allergy, but not SPT positivity. Independent inverse associations were found for early‐life exposures: at least weekly consumption of yoghurt with hayfever (odds ratio (OR) = 0.3, 95% confidence intervals (CI) 0.1–0.7) and allergic rhinitis (OR = 0.3, 95% CI 0.2–0.7); any unpasteurized milk consumption with atopic eczema/dermatitis syndrome (AEDS) (OR = 0.2, 95% CI 0.1–0.8); cats inside or outside with hayfever (OR = 0.4, 95% CI 0.1–1.0) and AEDS (OR = 0.4, 95% CI 0.2–0.8); dogs inside or outside with asthma (OR = 0.4, 95% CI 0.2–0.8); and pigs with SPT positivity (OR = 0.2, 95% CI 0.1–0.9).

Conclusions:Despite finding a protective effect of early‐life animal exposures, we found a greater prevalence of allergic disease on farms.
Isolation and characterization of Tha p 1, a major allergen from the pine processionary caterpillar Thaumetopoea pityocampa
Authors: Moneo I. , Vega J. M. , Caballero M. L. , Vega J. , Alday E.
Published: March 2003

Background: Pine processionary caterpillars induce dermatitis by a toxic–irritative mechanism. The existence of true allergic reactions to allergens from these caterpillars has been recently demonstrated by positive immediate skin prick tests and specific IgE determination by immunoblotting using crude larval extracts. The aim of this work was to purify allergens from the crude larval extract in order to characterize IgE‐binding proteins from these caterpillars.

Methods: Allergens were separated by ethanol gradient fractionation and reversed phase HPLC. The N‐terminal amino acid sequence of a selected allergen was obtained after SDS‐PAGE and transfer. The clinical relevance of this allergen was measured using sera from patients allergic to caterpillar.

Results: An allergen with a molecular weight close to 15 kDa was purified. It was recognized by 9 out of 11 allergic patients (82%). Its N‐terminal amino acid sequence had no homologies to any other protein already described in data bases. For this reason, no information about its biological function could be obtained.

Conclusions: This 15‐kDa IgE‐binding protein is a major caterpillar allergen and shows no homologies to other insect allergens already described.
A mouse model of the atopic eczema/dermatitis syndrome by repeated application of a crude extract of house‐dust mite Dermatophagoides farinae
Authors: Matsuoka H. , Maki N. , Yoshida S. , Arai M. , Wang J. , Oikawa Y. , Ikeda T. , Hirota N. , Nakagawa H. , Ishii A.
Published: March 2003

Background: We cultured Dermatophagoides farinae (Df), one of the most common mites in house dust and the most important allergen among natural allergens. With this material, we attempted to produce an animal model of the atopic eczema/dermatitis syndrome (AEDS).

Methods: We cultured Df mites in high density and prepared a crude extract of Df (DfE) together with the culture medium. We applied the extract to the back skin of NC/Nga and BALB/c mice three times per week for 8 weeks.

Results: In the NC/Nga group, dryness or scaling appeared on the skin, and scratching behavior increased at the second week in the DfE‐treated group. Skin erosion and hemorrhage occurred at the fourth week. The epidermis thickened and deepened into the upper dermis, in which mast cells were highly accumulated, corresponding with the skin lesion of AEDS patients. Specific IgE and IgG to DfE and total IgE were elevated in the sera. Mice treated with an extract of mite culture medium did not develop skin lesions. In the BALB/c group, mice developed specific IgE and IgG to DfE, however, no typical skin lesions appeared. Mast cells in the upper dermis did not increase.

Conclusions: Repeated painting of Dermatophagoides extract produced IgE‐associated AEDS‐like lesions on the skin of NC mice.
Decreased intercellular adhesion molecule‐1 (CD54) and L‐selectin (CD62L) expression on peripheral blood natural killer cells in asthmatic children with acute exacerbation
Authors: Lin S.‐J. , Chang L.‐Y. , Yan D.‐C. , Huang Y.‐J. , Lin T.‐J. , Lin T.‐Y.
Published: March 2003

Background: The capacity of inflammatory cells to adhere involves an array of adhesion molecules, and is critical to the inflammatory responses seen in childhood asthma. We aimed to determine the changes of intercellular adhesion molecule‐1 (ICAM‐1) and L‐selectin expressed on peripheral blood (PB) T lymphocytes and natural killer (NK) cells in asthmatic children with acute exacerbation and after prednisolone therapy.

Methods:  Flow cytometric analysis was performed to determine the expression of ICAM‐1 (CD54) and L‐selectin (CD62L) on T (CD3+) cells and NK (CD3–/CD56+) cells of PB from children with allergic asthma with acute exacerbation and in a stable condition after prednisolone therapy. Atopic subjects without asthma and age‐matched controls were also included for comparison.

Results:  Percentages of PB non‐CD3, CD56+ NK cells, but not CD3+ T cells, increased in asthmatic children with acute exacerbation, compared to those assessed in a stable condition after a course of prednisolone. However, significant decrease of ICAM‐1 (P = 0.01) and L‐selectin (P = 0.01) expression on PB NK cells, but not on T cells, were found in children with acute asthma compared to those in a stable condition. NK cells in children with acute asthma showed minimal expression of CD69 and CD25.

Conclusions:  Results suggests that either NK cells expressing ICAM‐1 and L‐selectin selectively migrated into inflamed lung tissues, or subsets of NK cells not expressing ICAM‐1/L‐selectin were expanded during acute exacerbation of childhood asthma.
A new oligomeric parvalbumin allergen of Atlantic cod (Gad mI) encoded by a gene distinct from that of Gad cI
Authors: Das Dores S. , Chopin C. , Villaume C. , Fleurence J. , Guéant J.‐L.
Published: March 2003

Background:  The major allergen of Baltic cod (Gadus callarias) is a 12.3‐kDa parvalbumin with two calcium‐binding sites corresponding to EF‐hand motifs. Our group found a 24‐kDa IgE‐reactive band that was also recognized by a monoclonal antiparvalbumin antibody in Atlantic cod (Gadus morhua). Our purpose was to purify and to determine the cDNA deduced sequence of this new cod allergen.

Methods:  Proteins from pre rigor mortis Atlantic cod were separated by gel filtration and the eluted peaks were analysed by SDS‐PAGE and Western blotting with sera of sensitized patients and with antiparvalbumin. Protein bands were microsequenced, RNA transcripts were amplified by reverse transcription and polymerase chain reaction (RT‐PCR) using primer combinations overlapping the open reading frame.

Results:  Four IgE and antiparvalbumin reactive proteins(12.5, 24, 38 and 51 kDa) were detected in gel filtration eluate. The cDNA deduced sequence of the 24 kDa protein had 109 amino acid residues with a molecular weight of 11.5 kDa and a theoretical pI of 4.34. The 24 kDa band corresponded therefore to a dimer of a β‐parvalbumin. Its homology was higher with Sal sI than with Gad cI. This new allergen was named Gad mI.

Conclusion:  We have characterized a new parvalbumin allergen in Gadus morhua. This protein formed oligomers in native and in reducing conditions. Gad mI and Gad cI may correspond to two distinct genes of Gadus species.
Drug allergy diagnosis work up
Authors: Demoly P. , Bousquet J.
Published: March 2003

Drug hypersensitivity reactions are a daily worry for clinicians. The tools allowing a definitive diagnosis are few and poorly validated. They include a thorough clinical history, standardized skin tests, reliable biological test, and sometimes drug provocation tests. These tools are currently being evaluated by the European Network of Drug Allergy, under the aegis of the EAACI drug hpersensitivity group of interest.
The role of house dust mite elimination in the management of childhood asthma: an unresolved issue
Authors: Boner A. , Pescollderungg L. , Silverman M.
Published: March 2003

Indoor allergens are likely to be direct environmental causes of asthma and mite exposure, and sensitization is the most important environmental risk factor for childhood asthma in temperate zones. Analagous to occupational asthma, allergen avoidance in asthmatic children sensitized and exposed to mite allergens is associated with a reduction in airway hyperresponsiveness and symptoms associated with improvement in lung function. The long‐term effect of this strategy needs to be prospectively evaluated considering both the timing and duration of exposure, as well as the timing and duration of removal. In order to be successful, it is important to achieve and maintain a major reduction on allergen levels, for a long period of time.
Associations of angiotensinogen gene mutations with hypertension and myocardial infarction in a gulf population
Authors: Frossard Philippe M , Hill Susan H , Elshahat Yassin I , Obineche Eniyoma N , Bokhari Awais M , Lestringant Gilles G , John Anne , Abdulle Abdishakur M
Published: March 2003

To date, the human angiotensinogen (AGT) gene and some of its variants represent the best examples of genetic influences that are involved in the determination of essential hypertension (EH) and associated cardiovascular diseases (CVDs). To assess the value of genotypingAGTin a genetically homogeneous population, we carried out a retrospective, case–control study of variants M235T and T174M for putative correlations with CVDs among nationals from the United Arab Emirates (Emirati) – an ethnic group characterized by no alcohol intake and no cigarette smoking.

We investigated a sample population of 229 Emirati (119 males and 110 females), comprising groups of controls and patients with clinical diagnoses of EH, left ventricular hypertrophy (LVH), ischaemic heart disease (IHD) and myocardial infarction (MI). M235T and T174M alleles were determined via assays based on the polymerase chain reaction. T174M showed no correlation with any of the four clinical entities included in this study. T235 alleles, however, occurred more frequently in the EH group and less frequently in the group of MI survivors. We also found that T235 allele frequencies decreased with age, indicating that in the Emirati population, T235 alleles are associated with a reduced life span and that this effect could occur through independent mechanisms underlying genetic susceptibilities to both EH and MI.
Autosomal recessive familial exudative vitreoretinopathy: evidence for genetic heterogeneity
Authors: de Crecchio Giuseppe , Simonelli Francesca , Nunziata Giuseppe , Mazzeo Salvatore , Greco Giovanni Maria , Rinaldi Ernesto , Ventruto Valerio , Ciccodicola Alfredo , Miano Maria Giuseppina , Testa Francesco , Curci Anna , D'Urso Michele , Rinaldi Maria Michela , Cavaliere Maria Luigia , Castelluccio Pia
Published: March 2003

Two unrelated families with familial exudative vitreoretinopathy (FEVR) show apparent autosomal recessive inheritance rather than the previously reported autosomal dominant or X‐linked recessive mode of inheritance. Compared with the other modes of inheritance, the inherited clinical features here include earlier onset (at birth) and a more severe progressive course.
Alternative splicing of exon 37 of FBN1 deletes part of an ‘eight‐cysteine’ domain resulting in the Marfan syndrome
Authors: McGrory Joel , Cole William G
Published: March 2003

A child and his father had the skeletal and cardiovascular manifestations of Marfan syndrome due to a heterozygous G+5→T transversion in intron 37 of the FBN1 gene. Cultured dermal fibroblasts preferentially used an alternative splice site in exon 37 that resulted in the loss of the 3′ 48 nucleotides of this exon. The translational reading frame was maintained with deletion of lysine 1568 to threonine 1582 and splitting of the codons for glycine 1567 and serine 1583 to yield GCC for alanine. The deletion removed two cysteine residues as well as a potential N‐linked oligosaccharide attachment site from the ‘8‐cysteine’ domain encoded by exons 37 and 38.
Ataxia‐telangiectasia, cancer and the pathobiology of the ATM gene
Authors: Meyn M. Stephen
Published: March 2003

Ataxia‐telangiectasia (A‐T) is a pleiotropic inherited disease characterized by neurodegeneration, cancer, immunodeficiencies, radiation sensitivity, and genetic instability. Although A‐T homozygotes are rare, the A‐T gene may play a role in sporadic breast cancer and leukemia. ATM, the gene responsible for A‐T, is homologous to several cell cycle checkpoint genes from other organisms. ATM is thought to play a crucial role in a signal transduction network that modulates cell cycle checkpoints, genetic recombination, apoptosis, and other cellular responses to DNA damage. New insights into the pathobiology of A‐T have been provided by the creation of Atm−/− mice and by in vitro studies of ATM function. Analyses of ATM mutations in A‐T patients and in sporadic tumors suggest the existence of two classes of ATM mutation: null mutations that lead to A‐T and dominant negative missense mutations that may predispose to cancer in the heterozygous state.
Partial trisomy 17p detected by spectral karyotyping
Authors: Morelli Susan H , Deubler Debra A , Brothman Lisa J , Carey John C , Brothman Arthur R
Published: March 2003

We report the case of a child with partial trisomy of the short arm of chromosome 17, which was characterized by 24‐color spectral karyotyping (SKY) and other fluorescence in situ hybridization (FISH) methods. The child had phenotypic features previously associated with trisomy 17p, including facial characteristics, developmental delay, postnatal growth retardation, single transverse crease, inguinal hernia, redundant neck skin folds, congenital heart defect, and club foot. This case illustrates the power of SKY for characterizing derivative/marker chromosomes in patients with rare cytogenetic syndromes.
Short rib‐polydactyly syndrome: more evidence of a continuous spectrum
Authors: Sarafoglou Kyriake , Funai Edmund F , Fefferman Nancy , Zajac Laura , Geneiser Nancy , Paidas Michael J , Greco Alba , Wallerstein Robert
Published: March 2003

We report a fetus with radiological features of the four established types of short rib‐polydactyly syndrome (SRPS). The phenotype of this fetus supports the previously suggested hypothesis that the different subtypes of the short rib and polydactyly syndrome are not single entities, but rather, part of a continuous spectrum with variable expressivity.
Multipaint FISH: a rapid and reliable way to define cryptic and complex abnormalities
Authors: Joyce Christine A , Ross Fiona M , Dennis Nicholas R , Wyre Nicholas D , Barber John Ck
Published: March 2003

We present the use of a multipaint fluorescence in situ hybridisation (FISH) approach for the detection and interpretation of chromosome abnormalities that could not be resolved by conventional cytogenetics alone. In case 1, a de novo add(Xp) was shown to be an unbalanced X;12 translocation; in case 2, a complex rearrangement involving a deletion of 5p was shown to include a previously undetected cryptic 5;6 translocation. In addition, in case 3, this technique defined additional complexities and nine breakpoints in an acquired rearrangement of chromosomes 2, 9, 11, 16 and 22 in a patient with myelodysplasia. The technique allows the simultaneous identification of up to 24 chromosomes on a single slide using FISH with directly labelled whole chromosome paints. This simple and rapid method does not require image enhancement, produces results within 48 h and, therefore, offers an alternative to other recent developments, such as combinatorial multifluor FISH, spectral karyotyping or comparative genomic hybridisation.
Genetic and environmental sources of QT interval variability in Israeli families: the kibbutz settlements family study
Authors: Friedlander Yechiel , Lapidos Tyrone , Sinnreich Ronit , Kark Jeremy D
Published: March 2003

QT interval prolongation not attributed to long QT syndromes is reported to be associated with increased risk of sudden and nonsudden cardiac death. Genetic and environmental determinants of QTc interval were investigated in an unselected free living population sample of 80 kindreds residing in kibbutz settlements in Israel.The sample included 214 males and 227 females aged 15–97 years. There was a significant familial aggregation of adjusted QT interval levels, as indicated by inter‐ and intraclass correlation coefficients significantly different from zero. Complex segregation analysis applied to the sex‐ and age‐adjusted data was not conclusive and heterogeneous etiologies for individual differences were suggested. There was evidence for a single recessive locus (q=0.173) with a major effect in addition to polygenic effects (h2=0.41) that explained the mixture of distributions. In parallel, a nontransmitted environmental major factor in addition to polygenic effects that explained the adjusted variation in QTc could not be rejected. Similar results were obtained upon the adjustment for sex, age, and environmental covariables. The major factor, either genetic or environmental, and polygenic‐loci accounted for about 20 and 33% of the adjusted QTc variation, respectively. Furthermore, sex, age, measured environmental covariables, the unmeasured major factor, and the unmeasured polygenes could account for 63% of the variation of QTc in these families.Our data provide evidence for a major factor, either genetic or environmental, in addition to a polygenic background, influencing QT interval levels in a population‐based sample of pedigrees.
Caspases and neurodegeneration: on the cutting edge of new therapeutic approaches
Authors: Wellington Cheryl L , Hayden Michael R
Published: March 2003

Unregulated apoptosis underlies many pathological conditions, including neurodegenerative diseases. In this review, we focus on the role of cysteine aspartate‐specific proteases (caspase) activity in Huntington disease (HD) and Alzheimer disease (AD) as two representative neurodegenerative disorders that normally manifest in mid‐ to late‐life. Caspases appear to be involved in the molecular pathology of HD by directly cleaving huntingtin and generating toxic protein fragments containing the polyglutamine tract, and by being recruited and activated by polyglutamine‐containing aggregates composed mainly of truncated huntingtin fragments. Several proteins involved in AD, including β‐amyloid precursor protein (APP) and presenilins (PSs), are also cleaved by caspases. For APP, caspase cleavage may contribute to toxicity by generating toxic fragments or by shifting APP processing toward an amyloidogenic pathway. For PSs, caspase cleavage disables antiapoptotic functions attributed to PS C‐terminal fragments. These observations suggest that caspases actively contribute to the molecular pathogenesis of these diseases and support the development of caspase inhibitors as potential therapeutic approaches for chronic neurodegenerative disorders.
Support for linkage of familial combined hyperlipidemia to chromosome 1q21–q23 in Chinese and German families
Authors: Pei Weidong , Baron Heike , Müller‐Myhsok Bertram , Knoblauch Hans , Ali Al‐Yahyaee Said , Hui Rutai , Wu Xigui , Liu Lisheng , Busjahn Andreas , Luft Friedrich C , Schuster Herbert
Published: March 2003

We examined familial combined hyperlipidemia (FCHL) families from nonisolated regions in Germany and China to see if we could corroborate support for a chromosome 1q FCHL locus in more general populations. We recruited 24 German families with 137 members, 92 of whom met the criteria of affected in terms of the low density lipoprotein (LDL) and triglyceride levels in excess of the 90th percentile for age and gender. In China, we recruited 12 families with a total of 81 members. All affected persons had total cholesterol concentrations> 240 mg/dl and triglyceride concentrations> 250 mg/dl. We examined the markers APOA2, D1S1677, D1S104, D1S194, D1S426, and D1S196. Two‐point linkage analysis allowing for heterogeneity gave a maximum linkage of disorder score (HLOD) of 2.60 right over D1S194, estimating the proportion of linked families at 36%. This marker is adjacent to D1S104. The evidence for linkage was roughly the same both in the German (HLOD 1.40) and Chinese families (HLOD 1.52). Marker D1S194 is close to the retinoid X receptor (RXR) gene locus, which was found to be linked to triglyceride levels in an earlier twin study from our laboratory. We interpret our observations as encouraging support for the recent findings indicating the presence of a gene for FCHL on chromosome 1q. Furthermore, since D1S194 is adjacent to the gene for the RXR, we suggest that RXR is an attractive candidate for involvement in FCHL.
Comparison of the role of dopamine, serotonin, and noradrenaline genes in ADHD, ODD and conduct disorder: multivariate regression analysis of 20 genes
Authors: Comings David E , Gade‐Andavolu Radhika , Gonzalez Nancy , Wu Shijuan , Muhleman Donn , Blake Hezekiah , Dietz George , Saucier Gerard , P MacMurray James
Published: March 2003

The present study is based on the proposal that complex disorders resulting from the effects of multiple genes are best investigated by simultaneously examining multiple candidate genes in the same group of subjects. We have examined the effect of 20 genes for dopamine, serotonin, and noradrenergic metabolism on a quantitative score for attention deficit hyperactivity disorder (ADHD) in 336 unrelated Caucasian subjects. The genotypes of each gene were assigned a score from 0 to 2, based on results from the literature or studies in an independent set of subjects (literature‐based scoring), or results based on analysis of variance for the sample (optimized gene scoring). Multivariate linear regression analysis with backward elimination was used to determine which genes contributed most to the phenotype for both coding methods. For optimized gene scoring, three dopamine genes contributed to 2.3% of the variance, p=0.052; three serotonin genes contributed to 3%, p=0.015; and six adrenergic genes contributed to 6.9%, p=0.0006. For all genes combined, 12 genes contributed to 11.6% of the variance, p=0.0001. These results indicate that the adrenergic genes play a greater role in ADHD than either the dopaminergic or serotonergic genes combined. The results using literature‐based gene scoring were similar. An examination of two additional comorbid phenotypes, conduct disorder and oppositional defiant disorder (ODD), indicated they shared genes with ADHD. For ODD different genotypes of the same genes were often used. These results support the value of the simultaneous examination of multiple candidate genes.
The molecular basis for developmental disorders of the pituitary gland in man
Authors: Dattani Mt , Robinson Ic
Published: March 2003

The development of the anterior pituitary gland is dependent upon a cascade of signalling molecules and developmental genes that function as transcription factors. Many of these genes are homeobox genes which contain a DNA‐binding region or homeobox. Animal models have given a valuable insight into human pituitary disease. For example, Pit‐1 and Prop1 mutants are known to have deficiencies of growth hormone, prolactin and thyroid‐stimulating hormone. Human phenotypes arising as a result of mutations in these genes are similar to the mouse mutants. Mutations in the novel homeobox gene Hesx1/HESX1 are associated with the highly variable phenotype of septo‐optic dysplasia in mouse and man. The unravelling of this complex developmental cascade is just commencing.
Mild phenotype in two siblings with distal monosomy 12p13.31→pter
Authors: Glass Ian A. , Trenholme Adrian , Mildenhall Lindsay , Bailey Richard J. , Cotter Philip D.
Published: March 2003

We report two sibs with trisomy for the region 2p25.1→pter and monosomy for the region 12p13.31→pter, due to adjacent‐1 segregation of a maternal balanced reciprocal translocation, 46,XX,t(2;12)(p25.1;p13.31). These sibs presented with a mild phenotype, but nevertheless showed features of each of the contributing aneusomies. Monosomy 12p has previously been considered to have a variable and indistinct phenotype. Comparison of these patients with previous reports showed that many features, including microcephaly, facial dysmorphia, developmental and growth delay and dental and digital anomalies are frequently associated with monosomy for 12p. Many of these features are common to other aneusomies, thereby mitigating against a distinct 12p monosomy syndrome at this time. However, the combination of digital and dental anomalies may suggest the presence of this particular monosomy. The proband and his sister had some of the more non‐specific features of 2p trisomy syndrome, and comparison with previous reports suggested that the characteristic 2p trisomy syndrome is more usually associated with larger or more proximal trisomies of 2p.
Multivariate analysis of associations of 42 genes in ADHD, ODD and conduct disorder
Authors: Comings David E , Gade‐Andavolu Radhika , Gonzalez Nancy , Wu Shijuan , Muhleman Donn , Blake Hezekiah , Chiu F , Wang E , Farwell K , Darakjy S , Baker R , Dietz George , Saucier Gerard , MacMurray James P
Published: March 2003

In a previous study (Comings DE et al. Comparison of the role of dopamine, serotonin, and noradrenergic genes in ADHD, ODD and conduct disorder. Multivariate regression analysis of 20 genes. Clin Genet 2000: 57: 178–196) we examined the role of 20 dopamine, serotonin and norepinephrine genes in attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD), using a multivariate analysis of associations (MAA) technique. We have now brought the total number of genes examined to 42 by adding an additional 22 candidate genes. These results indicate that even with the inclusion of these additional genes the noradrenergic genes still played a greater role in ADHD than any other group. Six other neurotransmitter genes were included in the regression equation – cholinergic, nicotinic, alpha 4 receptor (CHNRA4), adenosine A2A receptor (ADOA2A), nitric oxide synthase (NOS3), NMDAR1, GRIN2B, and GABRB3. In contrast to ADHD and ODD, CD preferentially utilized hormone and neuropeptide genes These included CCK, CYP19 (aromatase cytochrome P‐450), ESR1, and INS (p=0.005). This is consistent with our prior studies indicating a role of the androgen receptor (AR) gene in a range of externalizing behavors. We propose that the MAA technique, by focusing on the additive effect of multiple genes and on the cummulative effect of functionally related groups of genes, provides a powerful approach to the dissection of the genetic basis of polygenic disorders.
Analysis of sex chromosome aneuploidy in 41 patients with Turner syndrome: a study of ‘hidden’ mosaicism
Authors: Fernández‐García R , García‐Doval S , Costoya S , Pásaro E
Published: March 2003

We performed a genetic study of sex chromosome mosaicism in 41 Turner syndrome patients. The investigation was carried out in four phases: cytogenetics (G‐banding), FISH, PCR for SRY in all 41 cases, and sequencing of the SRY gene in the 2 patients with the Y chromosome.  The application of classical alpha‐satellite probes (CEP‐X and CEP‐Y), painting probes (WCP‐X and WCP‐Y) and also XIST, DXZ4 and two subchromosomal painting libraries (SCPL116 and SCPL102) covering the short and the long arm of the X chromosome, respectively, allowed us to find new mosaic cell lines (mosaicism) in 37 out of 41 patients; only 4 patients were defined as 45,X non‐mosaic. The most frequent hidden mosaic was 45,X/46,XX in 32% of the cases; the presence of isochromosomes comprised 25% and markers 5%. The patients who had been previously diagnosed as mosaics displayed a higher complexity in their karyotypes due to the presence of new cell lines.  The Y chromosome and the SRY gene were present in blood and ovarian tissue in 2 patients with karyotypes 45,X/46,XY and 45,X/46,X,idic(Ynf). In both patients, the sequencing of the SRY gene confirmed a nucleotide sequence identical to that of a control male. Our results support the hypothesis of ‘the necessity of mosaicism for survival’, and thus, a mitotic origin for this syndrome.
Single nucleotide polymorphisms and the future of genetic epidemiology
Authors: Schork Nicholas J , Fallin Daniele , Lanchbury Jerry S
Published: March 2003

In this review, we consider the motivation behind contemporary Single Nucleotide Polymorphism (SNP) initiatives. Many of these initiatives are projected to involve large, population‐based surveys. We therefore emphasize the utility of SNPs for genetic epidemiology studies. We start by offering an overview of genetic polymorphism and discuss the historical use of polymorphism in the identification of disease‐predisposing genes via meiotic mapping. We next consider some of the unique aspects of SNPs, and their relative advantages and disadvantages in human population‐based analyses. In this context, we describe and critique the following six different areas of application for SNP technologies:

Gene discovery and mapping.

Association‐based candidate polymorphism testing.

Diagnostics and risk profiling.

Prediction of response to environmental stimuli, xenobiotics and diet.

Homogeneity testing and epidemiological study design.

Physiologic genomics.

We focus on key issues within each of these areas in an effort to point out potential problems that might plague the use of SNPs (or other forms of polymorphism) within them. However, we make no claim that our list of considerations are exhaustive. Rather, we believe that they may provide a starting point for further dialog about the ultimate utility of SNP technologies. In addition, although our emphasis is placed on applications of SNPs to the understanding of human phenotypes, we acknowledge that SNP maps and technologies applied to other species (e.g. the mouse genome, pathogen genomes, plant genomes, etc.) are also of tremendous interest.