bluuebunny/crossref_metadata_2025 huggingface dataset:
School education and allergic sensitization in adults
Authors: Schäfer T. , Ruhdorfer S. , Weigl L. , Wessner D. , Heinrich J. , Wichmann H. ‐ E. , Ring J.
Published: March 2003

Background: There is evidence of an association between socioeconomic status (SES) and atopy mainly from studies in children which investigated atopic diseases and parental SES. We determined the association of allergic sensitization, as measured by skin prick test (SPT) and allergen‐specific IgE (RAST), and SES in a population‐based study in adults.

Methods: Within a population‐based, nested, case‐control study, a standardized interview was performed and allergic sensitization to common aeroallergens was determined by SPT and RAST.

Results: A total of 1537 adults (50.4% female, age: median 50.0, range 28‐78 years) were investigated, half of whom (50.2%) exhibited at least one positive RAST result according to the study design. SPT reactivity was 37.3% in this group and was estimated to be 26.1% in the representative study base of 4178 adults. Within increasing categories of school graduation (none; after 8, 10, 13, and >13 years), the prevalence of SPT (20.5%, 31.3%, 44.0%, 44.2%, 48.1%; P trend <0.0001) and RAST reactivity (35.0%, 48.0%, 52.3%, 48.4%, 58.4%; P trend=0.004) increased continuously. Similar results were obtained when testing this association on the level of single allergens. After control for age, sex, and parental history of atopic diseases, all but the first odds ratios for SPT remained significant (first category=reference, 2.06, 3.21, 3.88, 3.96). The same model for RAST reactivity revealed a similar result with effect estimate for the last category being significant (first category=reference, 1.89, 2.08, 2.10, 2.81).

Conclusions: Allergic sensitization (SPT and RAST) to common aeroallergens in adults follows a significant and linear association with school education.
Asthma and allergy in Russian and Norwegian schoolchildren: results from two questionnaire‐based studies in the Kola Peninsula, Russia, and northern Norway
Authors: Selnes A. , Odland J. Ø. , Bolle R. , Holt J. , Dotterud L. K. , Lund E.
Published: March 2003

Background: Previous studies have shown that the prevalence of asthma and allergy in children is lower in Eastern than Western Europe.

Methods: We have compared the prevalence of asthma, respiratory symptoms, allergic rhinoconjunctivitis, and atopic dermatitis in schoolchildren aged 7–13 years in a questionnaire‐based study conducted in the city of Nikel on the Kola Peninsula, Russia, in 1994 (n=1143) and another conducted in northern Norway in 1995 (n=8676).

Results: The prevalence of diagnosed asthma was 5.1% in Russian children and 8.6% in Norwegian children; RR=0.58 (95% CI: 0.44–0.76). The prevalence of all respiratory symptoms was higher in Russian children. The prevalence of allergic rhinoconjunctivitis was 16.9% in Russian children and 22.1% in Norwegian children: RR=0.74 (95% CI: 0.65–0.85). The prevalence of atopic dermatitis was 7.4% in Russian children and 19.7% in Norwegian children; RR=0.38 (95% CI: 0.31–0.46).

Conclusions: We conclude that the prevalence of diagnosed asthma, allergic rhinoconjunctivitis, and atopic dermatitis was higher in Norwegian than Russian schoolchildren. The higher prevalence of respiratory symptoms in Russian children probably reflects a higher prevalence of undiagnosed, nonallergic asthma.
Working with male rodents may increase risk of all_ergy to laboratory animals
Authors: Renström A. , Karlsson A.‐S. , Malmberg P. , Larsson P. H. , Van Hage‐Hamsten M.
Published: March 2003

Background: Our aim was to study the risk of laboratory animal all_ergy (LAA) among research staff working in laboratories separate from the animal confinement area. The roles of atopy and exposure intensity in LAA were studied with special regard to exposure to male rodents, who excrete higher levels of urinary all_ergens than female rodents.

Methods: Eighty rodent‐exposed subjects gave blood samples for the analysis of total IgE, Phadiatop, and specific IgE against rat (RUA) and mouse urinary all_ergens (MUA), and answered questionnaires. Air samples were collected for RUA and MUA aeroall_ergen measurement in both laboratories and animal confinement facilities.

Results: Twenty percent of the subjects had IgE >0.35 kU/l to RUA and/or MUA, and 32% had experienced animal work‐related symptoms, although 90% of aeroall_ergen samples from the research department laboratories were below the detection limit (<0.26 ng RUA per m3 and <0.8 ng MUA per m3). Atopy (positive Phadiatop), total IgE >100 kU/l, other all_ergies (especiall_y to other animals), or more than 4 years of exposure significantly increased laboratory animal sensitization and symptoms. Working with mainly male rodents gave odds ratios (95% CI) of 3.8 (0.97–15) for sensitization and 4.4 (1.4–14) for symptoms. Subjects with both exposure to mainly male rodents and atopy or elevated total IgE had a 10‐fold higher frequency of sensitization than exposed subjects with neither risk factor.

Conclusions: A majority of subjects with a combination of exposure to mainly male rodents and atopy or elevated total IgE developed sensitization to and symptoms from laboratory animals. Current low exposure seems to maintain the presence of specific IgE. Further measures must be undertaken to provide a safe workplace for laboratory animal workers.
Polyunsaturated fatty acids in maternal diet, breast milk, and serum lipid fatty acids of infants in relation to atopy
Authors: Kankaanpää P. , Nurmela K. , Erkkilä A. , Kalliomäki M. , Holmberg‐Marttila D. , Salminen S. , Isolauri E.
Published: March 2003

Background: The increased consumption of n‐6 polyunsaturated fatty acids (PUFA) has been shown to coincide with the increased prevalence of atopic diseases. We aimed to investigate whether maternal diet and atopic status influence the PUFA composition of breast milk and the serum lipid fatty acids of infants.

Methods: Maternal diet was assessed by a food questionnaire. The PUFA composition of breast milk obtained at 3 months from 20 allergic and 20 healthy mothers and of their infants' (10 atopic and 10 nonatopic/group of mothers) serum lipids was analyzed.

Results: Although no differences in maternal PUFA intake were observed, the breast milk of allergic mothers contained less γ‐linolenic acid (18:3 n‐6) than that of healthy mothers. Similarly, atopic infants had less γ‐linolenic acid in phospholipids than healthy infants, although n‐6 PUFA were elevated in other serum lipid fractions in atopic infants. The serum lipid fatty acids in atopic infants did not correlate with those in maternal breast milk.

Conclusions: Our results suggest that dietary n‐6 PUFA are not as readily transferred into breast milk or incorporated into serum phospholipids, but may be utilized for other purposes, such as eicosanoid precursors, in allergic/atopic individuals. Subsequently, high dietary proportions of n‐6 PUFA, or reduced proportions of regulatory PUFA, such as γ‐linolenic acid and n‐3 PUFA, may be a risk factor for the development of atopic disease.
Eosinophil cationic protein (ECP) in schoolchildren living in a mountainous area of Norway: a population‐based study of ECP as a tool for diagnosing asthma in children with reference values
Authors: Njå F. , Røksund O. D. , Carlsen K‐H.
Published: March 2003

Background: Most previous studies on eosinophil cationic protein (ECP) have been performed on carefully selected groups of asthmatic patients. Few studies based upon population cohorts have been reported. The primary objective of the present study was to assess the usefulness of serum eosinophil cationic protein (s‐ECP) in the diagnosis of asthma in schoolchildren and determine reference values based on measurements in healthy children.

Methods: The population consisted of 216 schoolchildren (aged 7–16 years) who in a previous questionnaire had reported asthma or asthma‐like symptoms and a control group. The questionnaire study comprised the entire population of schoolchildren in Upper Hallingdal. After clinical assessment, blood samples, and skin prick tests, these subjects were then reclassified into four groups: atopic and nonatopic asthmatic and nonasthmatics. S‐ECP was assessed in relation to atopy, asthma severity, allergen exposure, and sex.

Results: The asthma group (n=105) had significantly higher mean s‐ECP level than the nonasthma group (n=111) (13.3 vs 8.3 µg/l, P<0.001), with no significant difference between atopic asthmatics and atopic nonasthmatics. Mean s‐ECP levels in children with mild, moderate, or severe asthma were 12.1, 18.5, and 12.2 µg/l, respectively. The children with animal dander allergy demonstrated higher levels of s‐ECP than children without this allergy (12.9 vs 9.1 µg/l, P=0.001). The upper reference limit (determined as the 95th percentile in healthy children) of 19.1 µg/l, showed low sensitivity (24%) and high specificity (93%) for the diagnosis of asthma. The positive and negative likelihood ratios for the asthma diagnosis were found to be 3.2 and 0.83, respectively.

Conclusions: The highest s‐ECP values were found among children with moderate asthma. Animal dander allergy resulted in elevated s‐ECP. However, mean values were still below the reference value of 19.1 µg/l, and the sensitivity was low, suggesting that s‐ECP is not a useful parameter for diagnosing asthma in population‐based studies.
Diet, serum fatty acids, and atopic diseases in childhood
Authors: Dunder T. , Kuikka L. , Turtinen J. , Räsänen L. , Uhari M.
Published: March 2003

Background: The reasons behind the reported increase in the occurrence of childhood atopic sensitization rates are unclear. We wanted to evaluate the association between dietary fats, serum fatty acids, and the occurrence and development of atopic diseases.

Methods: From a longitudinal database of a population‐based sample, 231 sex‐ and age‐matched pairs in 1980 and 154 pairs in 1986 were chosen, between whom we compared the dietary data, serum fatty acid composition, and occurrence of atopic diseases. The same variables were also compared between those who developed atopic disease later and those who did not during the 9‐year follow‐up.

Results: Examination of the dietary data in 1980 for those who had developed atopic disease compared with those who had remained healthy showed that the atopic children had used less butter before the expression of atopy. According to the cross‐sectional data, the children with atopic disease consumed more margarine (mean 8.6 vs 7.3 [P=0.04]), and less butter (mean 9.4 vs 11.6 g/1000 kcal [P=0.002]), than the nonatopic children in 1980. Differences supporting these dietary findings were similarly found in the serum fatty acid data.

Conclusions: The diet of the atopic children differed from that of the nonatopic children in the consumption of polyunsaturated fat.
Cross‐reactivity of IgE antibodies to allergens
Authors: Aalberse R. C. , Akkerdaas J. , Van Ree R.
Published: March 2003

The cross‐reactivity of IgE antibodies is of interest for various reasons, three of which are discussed. Firstly, from the clinical view, it is important to know the patterns of cross‐reactivity, because they often (but not always) reflect the pattern of clinical sensitivities. We discuss the cross‐reactivities associated with sensitization to pollen and vegetable foods: PR‐10 (Bet v 1‐related), profilin, the cross‐reactive carbohydrate determinant (CCD), the recently described isoflavone reductase, and the (still elusive) mugwort allergen that is associated with celery anaphylaxis; cross‐reactivities between allergens from invertebrates, particularly tropomyosin, paramyosin, and glutathione S‐transferase (GST); and latex‐associated cross‐reactivities. Clustering cross‐reactive allergens may simplify diagnostic procedures and therapeutic regimens. Secondly, IgE cross‐reactivity is of interest for its immunologic basis, particularly in relation to the regulation of allergic sensitization: are IgE antibodies to allergens more often cross‐reactive than IgG antibodies to “normal” antigens? If so, why? For this discussion, it is relevant to compare not only the structural relation between the two allergens in question, but also the relatedness to the human equivalent (if any) and how the latter influences the immune repertoire. Thirdly, prediction of IgE cross‐reactivity is of interest in relation to allergic reactivity to novel foods. Cross‐reactivity is a property defined by individual antibodies to individual allergens. Quantitative information (including relative affinity) is required on cross‐reactivity in the allergic population and with specific allergens (rather than with whole extracts). Such information is still scarce, but with the increasing availability of purified (usually recombinant) allergens, such quantitative information will soon start to accumulate. It is expected that similarity in short stretches of the linear amino‐acid sequence is unlikely to result in relevant cross‐reactivity between two proteins unless there is similarity in the protein fold.
Systemic ketoconazole is an effective treatment of atopic dermatitis with IgE‐mediated hypersensitivity to yeasts
Authors: Lintu P. , Savolainen J. , Kortekangas‐Savolainen O. , Kalimo K.
Published: March 2003

Background: IgE‐mediated hypersensitivity to yeasts is often seen in atopic dermatitis (AD) patients, especially when dermatitis is located in the head, neck, and shoulder regions. Two studies have shown the efficacy of ketoconazole in the treatment of this type of AD, in contrast to results of topical treatment. The objective was to assess the clinical efficacy of antifungal treatment in AD in a randomized, double‐blind, placebo‐controlled study with oral ketoconazole and yeast‐specific IgE levels and saprophytic yeast growth monitored simultaneously.

Methods: Eighty patients with AD and positive P. ovale and/or C. albicans RAST/skin prick test results were randomized to receive ketoconazole or placebo for 30 days. The yeast growth of skin and pharynx; P. ovale, C. albicans, andS. cerevisiae RAST; serum total IgE; and the severity of the eczema (SCORAD) were assessed at day 0 and thereafter at 1 and 3 months.

Results: A significant improvement was seen in the SCORAD scale in the ketoconazole group at the second visit in comparison to the first visit (P<0.0005; n=36), but not in the placebo group (n=39). Of the individual determinants of the SCORAD, itching (P<0.005), the extent of dermatitis (area percentage), excoriation, lichenification (P<0.01), erythema, papulation, and dryness (P<0.05) improved significantly in the ketoconazole group. In the placebo group, only the extent of dermatitis (area percentage) decreased significantly (P<0.05). In the ketoconazole group, the number of positive P. ovale cultures decreased from 60% to 31% (n=35) compared to the placebo group (64% to 56%; n=39). The clinical response was most significant in female patients with positive yeast cultures.

Conclusions: Saprophytic yeasts may be a source of allergens in AD. Thus, patients with AD, yeast growth, and elevated IgE levels to yeasts should be offered antifungal treatment.
Sex‐related differences in the initiation of allergic rhinitis in mice
Authors: Yamatomo T. , Okano M. , Ono T. , Nakayama E. , Yoshino T. , Satoskar A. R. , Harn Jr D. A. , Nishizaki K.
Published: March 2003

Background: Several clinical and epidemiologic studies have investigated sex differences in the prevalence of allergic rhinitis. At present, however, no reports have demonstrated such differences in experimental models with local, but not parenteral, sensitization with antigens that may reflect natural exposure to allergens. We have recently developed murine models of allergic rhinitis after repeated intranasal sensitization with antigens in the absence of adjuvants. In this study, we investigated the role of sex in the initiation of the disease in vivo.

Methods: Male and female CBA/J and BALB/c mice were sensitized intranasally with phospholipase A2 (PLA2) and Schistosoma mansoni egg antigen (SEA), respectively, in the absence of adjuvants. After the repeated sensitization, serum Ab titers against the sensitizing antigen and nasal eosinophilia were determined. In addition, the involvement of androgen in IgE synthesis was investigated in castrated CBA/J male mice with or without testosterone administration.

Results: Females produced significantly higher levels of PLA2‐specific IgE than males in CBA/J mice sensitized with PLA2. On the other hand, both titers of PLA2‐specific IgG1 and nasal eosinophilia did not significantly differ between the two groups. Castrated male mice produced significantly higher amounts of PLA2‐specific IgE than sham‐treated male mice. In addition, PLA2‐specific IgE production decreased in castrated mice treated with testosterone. Sexual differences in the production of Ag‐specific IgE were not seen in BALB/c mice after the sensitization with SEA.

Conclusions: These results suggest that sex is responsible for the production of Ag‐specific IgE, but not IgG1 or nasal eosinophilia, and that androgen appears to be involved in the in vivo production of specific IgE in male mice.
Presence of fluticasone propionate on human nasal mucosal surface and in human nasal tissue over a period of 24 h after intranasal application
Authors: Bonsmann U. , Bachert C. , Delank K‐W. , Rohdewald P.
Published: March 2003

Background: Once‐daily use of nasally applied glucocorticoids was demonstrated to be effective in the treatment of allergic rhinitis. The aim of the study was to measure concentrations of fluticasone propionate (FP) in nasal secretion and nasal tissue over a period of 1 day after a single application of 100 µg FP.

Methods: Twenty‐six patients applied nasal FP spray at different time intervals before surgery. Cotton swabs, used to clean the mucosal surface, and resected nasal tissue were extracted. FP concentrations were determined by RIA.

Results: FP was found in nasal secretions in concentrations from 15 to 1 µg/g over a period of 20 h, and in nasal tissue in concentrations from 200 to 13 ng/g up to 24 h after the single application.

Conclusions: The long‐persisting high concentrations of FP provide the pharmacokinetic basis for once‐daily treatment.
Variations of serum eosinophil cationic protein and tryptase, measured in serum and saliva, during the course of immediate allergic reactions to foods
Authors: Vila L. , Sanz M. L. , Sánchez‐López G. , García‐Avilés C. , Diéguez I.
Published: March 2003

Background: Subjective complaints and reactions after placebo administration during food challenges (FC) may make their outcome difficult to interpret. We determined serum ECP and tryptase as tryptase in saliva during FC, looking for markers to support challenge outcomes.

Methods: Twelve patients with systemic reactions after food intake and nine presenting oral allergy syndrome (OAS) underwent skin tests; total and specific IgE determination; double‐blind, placebo‐controlled FC (DBPCFC); and open challenges. Blood samples were collected before and 1, 2, and 5 h after challenge and saliva before and 5, 30, and 60 min after challenge. ECP and tryptase were quantified by ImmunoCAP (Pharmacia‐Upjohn, Sweden). Serum tryptase of >10 µg/l was considered positive.

Results: After positive DBPCFC (n=8), ECP rose significantly (P<0.05) at 1‐h – 16.03 (12.8) μg/l (mean [standard deviation]) – and 2‐h intervals – 17.56 (10.7) μg/l – compared to basal level of 9 (6.4) μg/l. After negative DBPCFC (n=6), ECP increased from basal 9.63 (3.9) μg/l to 24.84 (14.17) μg/l at the 2‐h time point. There were nonsignificant differences in ECP between patients with positive and negative FC. Two patients with positive challenge showed a tryptase level of >10 µg/l and only one patient with OAS showed 5.6 µg/l of tryptase 5 min after FC.

Conclusions: ECP and tryptase in serum and saliva were not useful markers for FC outcomes.
Dose‐response and time course of specific IgE and IgG after single and repeated topical skin exposure to dry trimellitic anhydride powder in a Brown Norway rat model
Authors: Zhang X. D. , Murray D. K. , Lewis D. M. , Siegel P. D.
Published: March 2003

Background: Trimellitic anhydride (TMA)‐induced occupational asthma is thought to be associated with its ability to acylate proteins and to induce production of TMA‐specific immunoglobulin (Ig)E. Though the respiratory tract is considered to be a major exposure route leading to airway sensitization, the potential role of dermal exposure producing asthmatic sensitization is not known. The present study examines the ability of dry TMA powder to sensitize Brown Norway rats when applied, topically, to the skin.

Methods: A patch of hair was carefully clipped with scissors on the rat's back. Dry TMA powder (0.3, 1.25, 5 and 20 mg) was administered on days 0, 7, 14 and 21, and the area occluded with surgical tape overnight after each application. Residual powder recovered from the occluded skin was analyzed by proton nuclear magnetic resonance and was still predominantly TMA. Circulating anti‐TMA IgE and IgG were measured by ELISA.

Results: TMA elicited dose‐dependent production of specific IgE and IgG. Specific antibodies were detectable 2 weeks after the first TMA exposure and peaked between 3 and 4 weeks.

Conclusion: The data suggest that topical skin exposure to dry TMA powder can induce allergic/immunological sensitization as demonstrated by the production of specific antibodies.
Molecular cloning and sequence analysis of full‐length cDNAs encoding new group of Cyn d 1 isoallergens*
Authors: Au L.C. , Lin S.T. , Peng H.J. , Liang C.C. , Lee S.S. , Liao C.D. , Chang Z.N.
Published: March 2003

Background:  Cyn d 1, the major allergen of Bermuda grass pollen, contains some acidic/basic isoforms. The N‐terminal amino acid sequences of some acidic Cyn d 1 isoforms were found to be different from those of Cyn d 1 cDNA clones identified previously.

Methods: A predicted 17‐meric oligonucleotide probe was designed to fish the unidentified isoallergen cDNAs out of BGP cDNA library. The reactive clones were isolated and verified by sequencing. Two of them were expressed in the yeast Pichia pastoris to obtain recombinant Cyn d 1 proteins.

Results: All four cDNA clones encode the full‐length Cyn d 1 with mature proteins of 244 amino acid residues. A 97–99% identity was found among the deduced amino acids of these four clones while an 86% identity was elicited between the four clones and the ones previously identified. The predicted isoelectric focusing (pI) values of the newly identified Cyn d 1s are acidic while pIs of the previously identified Cyn d 1s are basic. The two recombinant acidic Cyn d 1 proteins possess the epitopes recognized by mouse and rabbit polyclonal anti‐Cyn d 1 antibodies, and have human IgE‐binding capacity as revealed by immunodot assay.

Conclusions: The present study identified full‐length cDNAs encoding new isoallergens of Cyn d 1, and separated Cyn d 1 gene into an acidic group and a basic group.
Severe IgE‐mediated anaphylaxis following consumption of fried frog legs: definition of α‐parvalbumin as the allergen in cause
Authors: Hilger C. , Grigioni F. , Thill L. , Mertens L. , Hentges F.
Published: March 2003

Background: IgE‐mediated allergic reactions to bullfrog and edible frog have been reported. The implicated allergens have not been defined so far. The frog material and the patient's serum from a case of severe food‐induced anaphylaxis were used to define the implicated allergen at the protein and DNA level.

Methods: Immunoblotting techniques and N‐terminal protein microsequencing were used to define the allergen recognized by the patient's serum. Back translation from the identified protein sequence was used to design degenerated primers to amplify the allergen's cDNA by polymerase chain reaction (PCR). We defined the nucleotide sequence of the allergen from the frog of Indonesian origin that was consumed by the patient, and the homologous cDNA from Rana esculenta.

Results: Protein microsequencing revealed that the implicated frog allergen belonged to the parvalbumin family. cDNAs coding for α‐ and β‐parvalbumin of R. esculenta and Rana species were cloned. Recombinant proteins were expressed in Escherichia coli. The patient's serum IgE antibodies recognized parvalbumin prepared from frog muscle and recombinant α‐parvalbumin from R. species but not from R. esculenta. Recombinant β‐parvalbumin was not recognized by the IgE antibodies.

Conclusion: This work defines at the protein and DNA levels α‐parvalbumin as the allergen implicated in a case of IgE‐mediated anaphylaxis to frog muscle. It also shows that a protein belonging to the parvalbumin family is implicated in type I allergies outside the fish species.
Adherence to asthma therapy in the preschool child
Authors: Rand C. S.
Published: March 2003

Preschool children's adherence to asthma therapy is often sub‐optimal and can result in decreased quality of life for children and parents, as well as an increased risk for dangerous asthma exacerbations. Asthma management for the preschool child presents some unique challenges to adherence to therapy, including the child's limited ability to communicate, multiple caregivers responsible for medications, and parental concerns about medications. Parent beliefs, characteristics of the regimen, and family functioning have been associated with adherence levels. Understanding and improving adherence to asthma therapy for the preschool child will necessarily require addressing these age‐specific concerns.
Unusual clinical features in an Angelman syndrome patient with uniparental disomy due to a translocation 15q15q
Authors: Fridman Cintia , Varela Monica C , Nicholls Robert D , Koiffmann Célia P
Published: March 2003

We had previously described a patient with an overgrowth syndrome and the chromosome constitution 45,XY,t(15q15q) (Wajntal et al., DNA Cell Biol 1993: 12: 227–231). Clinical reassessment and the use of molecular studies, including methylation analysis with an SNRPN probe, microsatellite analyses of D15S11, GABRB3 and D15S113 loci, and fluorescence in situ hybridization (FISH) using the SNRPN and GABRB3 probes, are consistent with a diagnosis of Angelman syndrome (AS) due to paternal isodisomy. This is the fourth report case of a translocation 15q15q with paternal uniparental disomy (UPD). Our findings suggest that some patients with clinical features of AS have hyperphagia and obesity with overgrowth, and that these features should not rule out a diagnosis of AS.
Kenny–Caffey syndrome: an Arab variant?
Authors: Sabry MA , Farag TI , Shaltout AA , Zaki M , Al‐Mazidi Z , Abulhassan SJ , Al‐Torki N , Quishawi A , Al Awadi SA
Published: March 2003

We describe 2 unrelated Bedouin girls who met the criteria for the diagnosis of Kenny–Caffey syndrome. The girls had some unusual features – microcephaly and psychomotor retardation – that distinguish the Kenny–Caffey syndrome profile in Arab children from the classical Kenny–Caffey syndrome phenotype characterized by macrocephaly and normal intelligence. The 2 girls did not harbor the 22q11 microdeletion (the hallmark of the DiGeorge cluster of diseases) that we previously reported in another Bedouin family with the Kenny–Caffey syndrome (Sabry et al. J Med Genet 1998: 35(1): 31–36). This indicates considerable genetic heterogeneity for this syndrome. We also review previously reported 44 Arab/Bedouin patients with the same profile of hypo‐parathyroidism, short stature, seizures, mental retardation and microcephaly. Our results suggest that these patients represent an Arab variant of Kenny–Caffey syndrome with characteristic microcephaly and psychomotor retardation. We suggest that all patients with Kenny–Caffey syndrome should be investigated for the 22q11 microdeletion. Other possible genetic causes for the Kenny–Caffey syndrome or its Arab variant include chromosome 10p abnormalities.
Additive effect of three noradrenergic genes (ADRA2A, ADRA2C, DBH) on attention‐deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects
Authors: Comings David E. , Gade‐Andavolu Radhika , Gonzalez Nancy , Blake Hezekiah , Wu Shuijuan , MacMurray James P.
Published: March 2003

Halperin et al. (Halperin JM, Newcorn JH, Koda VH, Pick L, McKay KE, Knott P. Noradrenergic mechanisms in ADHD children with and without reading disabilities: a replication and extension. J Am Acad Child Adolesc Psychiatry 1997: 36: 1688–1696) reported a significant increase in plasma norepinephrine (NE) in attention‐deficit hyperactivity disorder (ADHD) children with reading and other cognitive disabilities compared to ADHD children without learning disabilities (LD). We examined the hypothesis that ADHD±LD was associated with NE dysfunction at a molecular genetic level by testing for associations and additive effects between polymorphisms at three noradrenergic genes – the adrenergic α2A receptor (ADRA2A), adrenergic α2C receptor (ADRA2C), and dopamine β‐hydroxylase (DBH) genes. A total of 336 subjects consisting of 274 individuals with Tourette syndrome (TS) and 62 normal controls were genotyped. Regression analysis showed a significant correlation between scores for ADHD, a history of LD, and poor grade‐school academic performance that was greatest for the additive effect of all three genes. Combined, these three genes accounted for 3.5% of the variance of the ADHD score (p=0.0005). There was a significant increase in the number of variant NE genes progressing from subjects without ADHD (A−) or learning disorders (LD−) to A+LD− to A−LD+ to A+LD+ (p=0.0017), but no comparable effect for dopamine genes. These data support an association between NE genes and ADHD, especially in ADHD+LD subjects.
Biology of presenilins as causative molecules for Alzheimer disease
Authors: Nishimura Masaki , Yu Gang , St George‐Hyslop Peter H
Published: March 2003

Many missense mutations in the presenilins are associated with autosomal dominant forms of familial Alzheimer disease (AD). Presenilin genes encode polytopic transmembrane proteins, which are processed by proteolytic cleavage and form high‐molecular‐weight complexes under physiological conditions. The presenilins have been suggested to be functionally involved in developmental morphogenesis, apoptosis signal pathways, and processing of selected proteins including β‐amyloid precursor protein. Although the underlying mechanism in which presenilin mutations lead to development of AD remains elusive, one consistent mutational effect is an overproduction of long‐tailed amyloid β‐peptides. Furthermore, presenilins interact with β‐catenin to form presenilin complexes and presenilin mutations effect β‐catenin signalling pathways.
A common truncation variant of lipoprotein lipase (Ser447X) confers protection against coronary heart disease: the Framingham Offspring Study
Authors: Gagné Se , Larson Mg , Pimstone Sn , Schaefer Ej , Kastelein Jjp , Wilson Pwf , Ordovas Jm , Hayden Mr
Published: March 2003

Genetic variation at the lipoprotein lipase (LPL) locus has been shown to influence plasma lipids and to modulate risk of coronary heart disease (CHD). Recently, we found that the most frequent variant at this locus, involving a C‐terminal truncation of two amino acids (Ser447X), was associated with both higher LPL activity and high density lipoprotein cholesterol (HDL‐C) in patients with CHD. However, the impact of this S447X variant on lipids and CHD in the general population was hitherto unknown. We, therefore, analyzed a total of 1 114 men and 1 144 women randomly ascertained from the Framingham Offspring Study (FOS) for the presence of this LPL variant. Carrier frequency of the S447X allele was 17%, and in men carrier status was associated with higher total cholesterol (Δ=6.2 mg/dl, p=0.03), higher HDL‐C (Δ=2.3 mg/dl, p=0.01), and lower triglyceride (TG) levels (Δ=−19.4 mg/dl, p=0.02). Moreover, in men, the S447X allele conferred significant protection against CHD (odds ratio: 0.43; p=0.04). These effects on lipids and CHD were not seen in women. Our study represents the first report on the impact of this mutation on CHD in men from the general population, and we conclude, therefore, that the S447X variant may confer significant protection against high TG levels, low HDL‐C, and premature CHD in these subjects.
Epidemiology of dystrophinopathies in North‐West Tuscany: a molecular genetics‐based revisitation
Authors: Siciliano G , Tessa A , Renna M , Manca ML , Mancuso M , Murri L
Published: March 2003

A molecular genetics‐based epidemiological investigation was carried out in 1997 in the territory of North‐West Tuscany, central Italy, to calculate incidence and prevalence rates of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Results were compared with a previous epidemiological study conducted in the same area in 1981, in the pre‐dystrophin era. Routine adoption of methods of molecular diagnosis determined an increase in prevalence of BMD from 1.06×10−5 to 2.42×10−5 inhabitants, while cumulative incidence of DMD was markedly decreased from 23.12×10−5 during the period 1965–1976 to 10.71×10−5 male live births during the period 1977–1994. The combined reduction of DMD/BMD diagnostic error rate and familial recurrence could explain these results, providing the bases for a consistent redefinition of dystrophinopathy carrier frequency in the area considered.
Homozygosity for a novel DTDST mutation in a child with a ‘broad bone‐platyspondylic’ variant of diastrophic dysplasia
Authors: Mégarbané André , Haddad Fady A. , Haddad‐Zebouni Soha , Achram Mitri , Eich Georg , Le Merrer Martine , Superti‐Furga Andrea
Published: March 2003

Atypical or variant forms of well‐known chondrodysplasias may pose diagnostic problems. We report on a girl with clinical features suggesting diastrophic dysplasia but with unusual radiographic features including severe platyspondyly, wide metaphyses, and fibular overgrowth, which are partially reminiscent of metatropic dysplasia. The diagnosis was clarified by molecular analysis of the DTDST gene, which revealed homozygosity for a previously undescribed mutation leading to a Q454P substitution in the 10th transmembrane domain of the DTDST sulfate transporter. Molecular analysis may be of particular value in such atypical cases.
Association of pre‐eclampsia with common coding sequence variations in the lipoprotein lipase gene
Authors: A Hubel Carl , M Roberts James , E Ferrell Robert
Published: March 2003

Marked dyslipidemia may contribute to endothelial cell dysfunction in pre‐eclampsia. Carriers of N291S or D9N missense mutations in the lipoprotein lipase (LPL) gene exhibit reductions in LPL activity and are predisposed to dyslipidemia and cardiovascular disease. In Caucasians, the D9N variant is in strong linkage disequilibrium with the −93T→G promoter variant. A fourth LPL variant, S447X, is often associated with a beneficial lipid profile. We asked if the N291S and the combination D9N/−93T→G variants are more prevalent, and if the S447X variant is less prevalent, in Caucasian women with pre‐eclampsia as compared with normal pregnancies. DNA amplification was followed by an allele‐specific oligonucleotide ligation assay. Allele frequencies were analyzed with a χ2 table and Yates’ correction. The N291S variant was identified in 11.1% of pre‐eclamptics as compared with 2.9% of pregnancy controls (p=0.008). All carriers of D9N were also carriers of −93T→G. The D9N/−93T→G combined variant was found in 7.1% of pre‐eclamptics as compared with 1.4% of pregnancy controls (p=0.02). No individuals were carriers of both N291S and D9N/−93T→G. Thus, 18.2% of pre‐eclamptics had either of these LPL mutations compared with 4.3% of pregnancy controls (and 4.4% of population controls). The frequency of the S447X variant did not differ among groups. We conclude that carriers of N291S or combined D9N/−93T→G mutations in the LPL gene are at substantially increased risk of pre‐eclampsia.
Two common mutations (D9N, N291S) in lipoprotein lipase: a cumulative analysis of their influence on plasma lipids and lipoproteins in men and women
Authors: Kastelein John Jp , Ordovas Jose M , Wittekoek Marianne E , Pimstone Simon N , Wilson Peter Wf , Gagné S Eric , Larson Martin G , Schaefer Ernest J , Boer Jolanda Ma , Gerdes Christian , Hayden Michael R
Published: March 2003

We assessed the effect of two common mutations in the lipoprotein lipase gene (LPL), D9N and N291S, which have been shown to modulate plasma lipids in a wide spectrum of patients.A total of 1 114 men and 1 144 women from the Framingham Offspring Study (FOS) were analyzed for these two LPL variants. Subsequently, the association with fasting plasma lipids and risk of coronary artery disease (CHD) was determined. We extended our study by calculating weighed means of lipids and lipoproteins in carriers and non‐carriers for these LPL mutations in patients with genetic dyslipidemias, CHD patients and healthy controls.In the FOS sample, the D9N and N291S alleles were associated with lower high‐density lipoprotein‐cholesterol (HDL‐C) (Δ=−0.07 mmol/l, p=0.03) and a trend towards increased triglycerides (Δ=0.25 mmol/l, p=0.07). In women, a trend towards the high triglyceride, low HDL‐C phenotype was evident (Δ=−0.02 mmol/l for HDL‐C and Δ=0.14 mmol/l for triglycerides, respectively). Cumulative analysis of other studies of male carriers of the D9N and N291S revealed higher levels of triglycerides (D291N; 2.60(1.85) mmol/l vs. 1.62(1.18) mmol/l: p<0.0001) (D9N; 1.94 (1.19) mmol/l vs. 1.74(1.17) mmol/l: p<0.001) and lower HDL‐C (N291S; 1.04(0.32) mmol/l vs. 1.15(0.28) mmol/l: p<0.0001) (D9N; 1.08(0.24) mmol/l vs. 1.16(0.28) mmol/l: p<0.0001). In females, results differed with higher TG levels (N291S; 1.70(0.99) mmol/l vs. 1.10(0.63) mmol/l: p<0.001) (D9N; 1.08(0.76) mmol/l vs. 0.96(0.51) mmol/l: p<0.01) and lower HDL‐C levels (N291S; 1.27(0.33) mmol/l vs. 1.51(0.32) mmol/l: p<0.0001); however, the HDL‐C levels for D9N carriers were similar to non‐carriers (D9N; 1.52(0.29) mmol/l vs. 1.53(0.35) mmol/l: p=0.83).Our data provide evidence that common variants of the LPL gene are significant modulators of lipid and lipoprotein levels in both men and women.
‘New’ manifestations of BOR syndrome
Authors: Weber Karen M , Kousseff Boris G
Published: March 2003

Defined in 1975, branchio‐oto‐renal (BOR) syndrome is an autosomal dominant disorder consisting of branchial arch anomalies, hearing loss, and urinary tract malformations. It is the prototype of the non‐chromosomal syndromes that have branchial arch anomalies as major clinical manifestations: BOR, branchio‐otic (BO), branchio‐otic‐facial (BOF), and Townes–Brock syndromes. Subsequently, several clinical manifestations have expanded its phenotype. Retrospective analysis of 31 020 families evaluated between January 2, 1982 and December 31, 1996 at the genetic clinics of the University of South Florida, showed seven probands with BOR/?BOR syndrome. Four of the probands and affected relatives had manifestations that further expanded the phenotype: gustatory lacrimation, hypospadias, imperforate anus, osteosclerosis, microcephaly, hypodontia, congenital vocal cord paresis, and congenital incomplete fixation of the transverse colon. Thus, BOR/?BOR syndrome appears to be a clinically and genetically heterogeneous multiorgan/system entity that manifests itself predominantly during organogenesis. Clinicians and researchers alike should be cognizant of the expanded phenotype and heterogeneity, while in the DNA laboratories the latter will be sorted out.
The malformed kidney: disruption of glomerular and tubular development
Authors: Piscione Tino D , Rosenblum Norman D
Published: March 2003

Renal malformations are the major cause of renal failure during early childhood. They are found in approximately 100 genetic syndromes. We review the embryologic development of the kidney and its molecular control. Important new information has been derived from mutational analysis in humans and mice. We describe how mutations in nine transcription factors, 12 signaling molecules and nine gene products involved in a variety of other cellular functions disrupt renal morphogenesis. The information presented provides a template for integrating new discoveries on the molecular basis of renal development, for classifying renal malformations observed in the clinical setting, and for identifying defective genes in affected patients.
Association between polymorphism of the cholecystokinin gene and idiopathic Parkinson's disease
Authors: Fujii C , Harada S , Ohkoshi N , Hayashi A , Yoshizawa K , Ishizuka C , Nakamura T
Published: March 2003

Parkinson's disease (PD) is characterized by major alterations of neurotransmitter activity due to damage of the substantia nigra. Changes in neuropeptide concentration within the basal ganglia may play an important role in the putative dopaminergic–peptidergic interactions associated with the disease. Cholecystokinin (CCK) modulates the release of dopamine in the mesolimbic pathway and affects dopamine‐related behavior.We analyzed genetic variations in the CCK gene, in both the coding and promoter region, in order to investigate the role of polymorphism in idiopathic PD. Four polymorphic sites of the CCK gene (‐196G/A, ‐45C/T, 1270C/G, 6662C/T) were found in PD patients and controls. Complete linkage disequilibrium was observed between the ‐45 locus and the 1270 locus, and also a possible linkage disequilibrium was found between the ‐45 and ‐196 loci. A significant difference was found in the distributions of three identified genotypes at the ‐45 locus between 116 PD patients and 95 age‐matched control subjects (χ2=7.95, p=0.018, Bonferroni correction; p=0.054). In addition, a significant difference was obtained amongst the three genotypic groups at the ‐45 locus when compared between PD patients who experienced hallucinations (n=23) and those (n=93) who did not (χ2=8.08, p=0.018, Bonferroni correction; p=0.126).Our data suggested that mutations at the ‐45 locus in the promoter region of the CCK gene may influence vulnerability to hallucinations in PD patients treated with l‐dopa.
Clinical variability of Larsen syndrome: diagnosis in a father after sonographic detection of a severely affected fetus
Authors: Becker R , Wegner R‐D , Kunze J , Runkel S , Vogel M , Entezami M
Published: March 2003

Larsen syndrome shows a broad spectrum of clinical manifestation ranging from a lethal form of the disorder to a mild clinical expression with absence of major diagnostic features. Here we show that even intrafamilial manifestation may vary extremely to the point that Larsen syndrome in a father has been diagnosed only by typical sonographic features in an affected fetus.
Gender‐specific effects of NAT2 and GSTM1 in bladder cancer
Authors: Schnakenberg E , Lustig M , Breuer R , Werdin R , Hübotter R , Dreikorn K , Schloot W
Published: March 2003

One approach for risk assessment of cancer is the evaluation of polymorphic enzymes involved in cancer using molecular tools. Phase II enzymes are involved in the detoxification of several drugs, environmental substances and carcinogenic compounds. Here, we analyzed enzymes for their putative relevance in urinary bladder cancer. The hereditable enzyme polymorphism of arylamine N‐acetyltransferase 2 (NAT2) and glutathione S‐transferase M1 (GSTM1) and T1 (GSTT1) was studied in 157 hospital‐based patients and in 223 control subjects. Slow acetylation was not observed to be a significant risk factor of developing bladder cancer (OR: 1.33; 95% CI 0.85–2.09). One genotype responsible for slow acetylation (NAT2*5B/*6A) was observed significantly more frequently in bladder cancer patients compared with control subjects (OR: 1.63; 95% CI 1.03–2.58).  Gender‐specific effects were observed when patients were divided into subgroups. In male patients, slow acetylators were identified as carrying a significant increased risk of developing bladder cancer, in particular when the genotype NAT2*5B/*6A was combined with the GSTM1 null genotype (OR: 4.39; 95% CI 1.98–9.74). By contrast, the same genotype combination significantly protected female patients from bladder cancer (OR: 0.21; 95% CI 0.06–0.80).
Neuronal migration defects of the cerebral cortex: a destination debacle
Authors: Uher Brian F , Golden Jeffrey A
Published: March 2003

Disruptions in neuronal migration have been postulated as the basis for many cerebral malformations including lissencephaly, cortical heterotopia, and double cortex. Recently, the genetic basis for some of these disorders has been identified. In this review, we highlight recent advances in our understanding of the molecular mechanisms of neuronal migration and its relationship to cerebral cortical development and neuronal migration disorders. This has allowed us to begin categorizing specific malformations based on their molecular etiology.
United Kingdom experience with presymptomatic testing of individuals at 25% risk for Huntington's disease
Authors: Benjamin Cm , Lashwood A
Published: March 2003

Between 1994 and 1998, the 23 UK genetics departments, which form the UK Huntington's Disease Consortium, have undertaken 161 direct mutation adult predictive tests on individuals whose at‐risk parent was alive or had died without showing signs of Huntington's disease (HD) (5.7% of total UK tests). This study describes the number of requests for 25% risk predictive testing for HD in 1994 (the first year in which direct testing was available in the UK), and also a descriptive survey of the first 85 tests.  In total, 85 tests were performed in the first 2 years of direct mutation testing, ten (11.8%) tests were mutation positive, 73 (85.9%) were negative and two (2.3%) were equivocal. The at‐risk parent was alive in 54 (63.5%) cases. Four of the ten mutation positive candidates had parents who were alive and therefore received a prediction through their child. All centres included a discussion about the effect of testing on the 50% at‐risk parent and all offered to see the parent for counselling.  Of the 87 applicants for testing during 1994, 31 (35.6%) withdrew, this is higher than the 25% withdrawal rate for the 50% risk candidates. The candidates who withdrew were significantly younger and had more parents who were alive than those who continued with testing. Seven of the 31 candidates who withdrew from testing had at‐risk parents who decided to be tested in the first instance. During the counselling process, issues were raised relating to pre‐test agreements and family secrecy. This study indicates the importance of pre‐test counselling and the involvement of the parent in the counselling process. 25% risk testing for HD is now being offered in the majority of UK centres. As more genes are identified for late‐onset conditions, it is important that the complexities of 25% risk testing for late‐onset conditions are not underestimated. This limited survey does not investigate how individual families cope with the psychological and social issues raised by this study and further research in this area is needed.
Predictive testing for familial adenomatous polyposis in a rural South Indian community
Authors: Savithri Hs , Venkatesha Murthy Hs , Baskaran G , Appaji Rao N , Kool D , Edkins E , Wang W , Bittles Ah
Published: March 2003

During the course of genome studies in a rural community in the South Indian state of Karnataka, DNA‐based investigations and counselling for familial adenomatous polyposis (FAP) were requested via the community physician. The proposita died in 1940 and FAP had been clinically diagnosed in 2 of her 5 children, both deceased. DNA samples from 2 affected individuals in the third generation were screened for mutations in theAPCgene, and a frame‐shift mutation was identified in exon 15 with a common deletion at codon 1061. Predictive testing for the mutation was then organized on a voluntary basis. There were 11 positive tests, including confirmatory positives on 2 persons diagnosed by colonoscopy, and to date surgery has been successfully undertaken on 3 previously undiagnosed adults. The ongoing success of the study indicates that, with appropriate access to the facilities offered by collaborating centres, predictive testing is feasible for diseases such as FAP and could be of significant benefit to communities in economically less developed countries.