bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival of memory T cells specific for Japanese cypress pollen allergen is maintained by cross‐stimulation of putative pectate lyases from other plants
Authors: Nakamura Y. , Takagi S. , Suzuki M. , Ito H. , Murakami S. , Ohta N.
Published: March 2003

In view of recent studies on the mechanisms of the survival of peripheral memory T cells, we tested the biologic role of pectate lyase, a pectin‐degrading enzyme, as the cross‐reactive antigen required for the recurring survival signals for human T cells specific for Cha o 1, a pollen allergen molecule of the Japanese cypress. We determined a 16‐mer epitope peptide for the T‐cell clone, and prepared synthetic oligopeptides of homologous regions in putative pectate lyase of other plants. Of these homologous peptides, ZePel (Zinnia elegans), ban 17 (banana), and Amb a 1.1 (short ragweed) induced strong proliferative responses of the Cha o 1‐specific T‐cell clone in vitro. In addition, suboptimal doses of peptide homologs derived from banana and short ragweed enhanced the survival potency of this T‐cell clone without detectable proliferative responses to the peptides. When there was no antigen stimulation, the T‐cell clone decreased in viable cell number and lost antigen‐specific proliferation activity on day 6 during in vitro incubation. On the other hand, T‐cell clones incubated with these survival‐inducing peptides maintained proliferative activity to Cha o 1 even on day 9. Serum derived from the donor patient did not contain detectable levels of IgE specific to banana or short ragweed by CAP‐RAST. These results show that human T cells specific for pollen allergen seem to use cross‐reactive pectate lyase peptides to deliver survival signals even in the absence of pollen allergen, and memory T cells maintained in such a manner might be functioning at the onset of allergic pollinosis, although pollen allergens are seasonal.
The prevalence of CMA/CMPI in young children: the validity of parentally perceived reactions in a population‐based study
Authors: Eggesbø M. , Botten G. , Halvorsen R. , Magnus P.
Published: March 2003

Background: The present study aimed to estimate the prevalence of adverse reactions to milk, as population‐based prevalence estimates based on objective diagnostic procedures are rare.

Methods: Children with parentally reported reactions to milk were selected for further examination from a population‐based cohort of 2721 children. At the age of 2½ years, they underwent a stepwise diagnostic procedure that included diet trials at home, skin prick tests, and open and double‐blind, placebo‐controlled food challenges. A sample of children with symptoms not attributed to milk was selected for assessment of unrecognized reactions.

Results: The estimated point prevalence of cow's milk allergy and cow's milk protein intolerance (CMA/CMPI) in children with parentally perceived reactions at the age of 2½ years was estimated to be 1.1% (CI 0.8–1.6). However, this was an underestimate, as unrecognized reactions were detected. Most reactions were not IgE‐mediated. The positive predictive value of a parentally perceived reaction depended on the number of times it had been reported and was good for reactions reported three times (at 12, 18, and 24 months of age).

Conclusions: The present study confirms previous findings that parents overestimate milk as a cause of symptoms in their children; however, it also indicates that unrecognized reactions may be a problem as well.
Specific IgE antibodies to peanut in western Sweden – has the occurrence of peanut allergy increased without an increase in consumption?
Authors: Van Odijk J. , Ahlstedt S. , Bengtsson U. , Hulthén L. , Borres M.P.
Published: March 2003

Background: Sensitization to peanut has seldom been investigated in Sweden. Therefore, all IgE‐specific tests for peanut during a 5‐year period were reviewed to study the relation between the levels of specific IgE antibody to peanut and age, sex, symptoms, and other atopic manifestations.

Methods: All serum samples were analyzed for IgE antibodies to peanut in relation to sex, age, clinical reactions, and other food allergens. A subgroup was asked to answer a questionnaire about symptoms and atopic manifestations in relation to IgE antibody levels.

Results: During the study period, 2417 tests were made for peanut. There was an increased prevalence of detectable IgE antibodies during the years studied. More than 80 individuals under 2 years of age were sensitized to peanut. In the subgroup, individuals with detectable IgE antibodies reported a shorter reaction time after eating peanuts than individuals with normal IgE antibody levels (P<0.05).

Conclusions: The reaction pattern to peanuts in Sweden is similar to that in many other countries despite a reported steady and low consumption. The severity of symptoms was connected to age and IgE antibody level. Patients with normal or low IgE antibody levels were not always free of symptoms even though their risk of allergic symptoms was reduced.
Urine eosinophil protein X (EPX) is an in vitro parameter of inflammation in atopic dermatitis of the adult age
Authors: Breuer K. , Kapp A. , Werfel T.
Published: March 2003

Background: Eosinophils are important effector cells in several atopic diseases. The levels of eosinophil granule‐derived mediators (ECP, EPX) in serum and body fluids have been proven to be correlated with disease activity in atopic respiratory diseases and atopic dermatitis. The study aimed to demonstrate an interrelationship between urine EPX and disease activity in adult patients with atopic dermatitis.

Methods: We determined urine EPX concentration, serum ECP concentration, and peripheral blood eosinophil count in 40 adult patients with mild to severe atopic dermatitis and compared it with the disease activity as assessed with the SCORAD index.

Results: Urine EPX and serum ECP concentrations were significantly higher in patients with severe atopic dermatitis than in patients with mild or moderate disease (median values 123.5 vs 78.3 µg/mmol creatinine, P<0.0001; 25.4 vs 14.9 µg/l, P<0.0001, respectively). We found a significant correlation between urine EPX levels, serum ECP levels, and the SCORAD (r=0.36, P<0.0001 and 0.34, P<0.0001, respectively).

Conclusions: Urine EPX is a useful in vitro parameter of inflammation in atopic dermatitis of the adult age.
Childhood farm environment and asthma and sensitization in young adulthood
Authors: Kilpeläinen M. , Terho E. O. , Helenius H. , Koskenvuo M.
Published: March 2003

Background: Farm environment in childhood may protect against sensitization, allergic rhinitis, and asthma.

Methods: Subjects were obtained from 10 667 Finnish first‐year university students who responded to a questionnaire survey on IgE‐mediated diseases. Two random samples were selected from 1631 respondents in Turku: subjects with asthma or wheezing, and subjects without asthmatic symptoms. A total of 296 subjects (72%) participated. Skin prick tests (SPT), measurements of IgE‐antibodies, methacholine challenge, and bronchodilation tests were performed. Weighted occurrence of current asthma and sensitization among students from “childhood farm” and “childhood nonfarm” environments were analyzed.

Results: Current asthma was found in 3.1% of subjects with childhood farm environment, and in 12.4% with nonfarm environment (odds ratio (OR) 0.22; 95% confidence interval (CI) 0.07–0.70). There were fewer positive SPT to birch (8.3 vs. 24.2%, OR 0.28, 95% CI 0.07–1.15) and timothy pollen (12.6 vs. 30.3%, OR 0.33, 95% CI 0.09–1.20) among subjects with childhood farm environment, but more sensitization to house‐dust mite (22.0 vs. 4.9%, OR 5.43, 95% CI 1.60–18.46). Sensitization to cat (RAST class ≥ 3) was less common in subjects with farm compared to nonfarm environments in childhood (1.5 vs. 13.1%; OR 0.10, 95% CI 0.02–0.47).

Conclusions: Farm environment in childhood protects against adult asthma and sensitization—especially to cat—the most important asthma related allergen. In contrast, sensitization to house‐dust mite was more common in farming subjects.
Oral antibiotic adverse reactions after penicillin skin testing: multi‐year follow‐up
Authors: Macy E. , Burchette R. J.
Published: March 2003

Background: Long‐term follow‐up data on adverse drug reactions after oral antibiotic use in penicillin allergy history positive individuals with penicillin skin test done in advance of need are rare.

Methods: Oral antibiotic associated adverse drug reactions in 83 penicillin skin test positive individuals were compared to a sex, age, and length of follow‐up matched sample of 166 penicillin skin test negative individuals, all of whom had at least one post penicillin skin test oral antibiotic. The mean post penicillin skin test follow‐up interval was 34.5 ± 16.6 months. There were 1655 total oral antibiotic exposures.

Results: In penicillin skin test positive individuals, the adverse drug reaction rate was not significantly different with cephalosporin or non‐beta‐lactam use (P = 0.12). In penicillin skin test negative individuals the adverse drug reaction rate was significantly lower with cephalosporin vs. non‐beta‐lactam use (P = 0.005). Penicillin was safely used in penicillin skin test negative individuals. Overall cephalosporins caused fewer adverse drug reactions independent of penicillin skin test status (P = 0.005).

Conclusions:   Penicillin skin testing was only able to predict penicillin associated adverse drug reactions in penicillin skin test positive individuals. Excluding accidental penicillin exposure in penicillin skin test positive individuals, non‐beta‐lactams were associated with adverse drug reactions more often than penicillins or cephalosporins, independent of the penicillin skin test result. Cephalosporins were used as or more safely than non‐beta‐lactams in both penicillin skin test positive and negative individuals.
Hemin, a heme oxygenase substrate analog, both inhibits and enhances neutrophil random migration and chemotaxis
Authors: Andersson J. A. , Uddman R. , Cardell L.‐O.
Published: March 2003

Background: Carbon monoxide (CO), is an endogenously produced gas, generated by the rate‐limiting enzyme heme oxygenase (HO), present in man throughout the respiratory tract. CO can elicit important physiological responses like bronchial relaxation and vasodilation. Both HO expression and CO levels in the airways increase in response to hypoxic challenge and to a wide variety of inflammatory stimuli, such as intermittent allergic rhinitis, asthma and upper respiratory tract infections. A role for CO in airway regulation and inflammation has therefore been suggested. However, information about CO‐induced effects on cells involved in airway inflammation is scarce. The present study was designed to investigate if the HO substrate analog hemin could affect neutrophil random migration, and N‐formyl‐L‐methionyl‐L‐leucyl‐L‐phenylalanine (fMLP) induced chemotaxis.

Methods: Hemin was added to and incubated with whole blood and the effects of the anticipated CO production were then evaluated on isolated neutrophils using a chemotaxis chamber.

Results: A biphasic dose–response curve emerged for both the neutrophil spontaneous random migration and the fMLP‐induced chemotaxis. Low concentrations of hemin (10−11 m to 10−9 m) enhanced the migratory response, whereas higher concentrations (10−7 m and 10−5 m) inhibited migration. The inhibition induced by hemin on fMLP‐induced migration was abolished after pre‐treatment with Rp‐8Br‐cyclicGMPS, an inhibitor of cyclicGMP.

Conclusions: The present data indicate that endogenously produced CO can affect both spontaneous and stimulated neutrophil migration, partly via a cyclicGMP‐related process, hence strengthening the idea of a role for CO in airway inflammation.
Recombinant fish parvalbumins: Candidates for diagnosis and treatment of fish allergy
Authors: Swoboda I. , Bugajska‐Schretter A. , Valenta R. , Spitzauer S.
Published: March 2003

Fish and fish products represent one of the most important causes of IgE‐mediated food hypersensitivity. In sensitized individuals contact with and consumption of fish can lead to severe health problems, ranging from urticaria and dermatitis to angiedema, diarrhoea, asthma and, at worst, systemic anaphylactic reactions and death. Parvalbumin, a small calcium‐binding protein present in the muscles of vertebrates, was identified as the major fish allergen. We describe the isolation and characterization of cDNA clones coding for carp parvalbumin by IgE immunoscreening of a carp muscle expression library. These clones will be the basis for the production of recombinant carp parvalbumin, a useful tool for in vitro and in vivo diagnosis of fish allergy.
Nerve growth factor and asthma
Authors: Bonini S. , Lambiase A. , Properzi F. , Bresciani M. , Sacerdoti G. , Bonini S. , Aloe L.
Published: March 2003

An increasing body of evidence shows that nerve growth factor (NGF) exerts biological activity not only on the central and peripheral nervous system, but also on the immune system thereby influencing allergic diseases and asthma.

(1) NGF circulating levels are increased in patients with allergic diseases and asthma, and are related to the severity of the inflammatory process and disease. In vernal keratoconjunctivitis, NGF plasma levels correlate with the number of mast cells infiltrating the conjunctiva, and NGF mRNA is increased in nasal mucosal scrapings of patients with allergic rhinitis who have high levels of NGF in serum and nasal fluids; NGF is further increased in nasal fluids after specific allergen challenge.

(2) NGF is produced and released by several modulatory and effector cells of allergic inflammation and asthma, for example T‐helper 2 lymphocytes, mast cells and eosinophils.

(3) NGF receptors are expressed on the conjunctival epithelium of patients with allergic conjunctivitis and the number of NGF‐receptor positive cells is increased in the conjunctiva of these patients. Indeed, local administration of NGF induces fibroblast activation and healing processes of human corneal ulcers, which suggests that NGF plays a role in tissue remodelling processes occurring in asthma.

(4) NGF increases airway hyperreactivity to histamine in an animal model of asthma, while anti‐NGF treatment reduces airway hyperreactivity induced by ovalbumin topical challenge in the sensitized mouse.
Thalassemia carrier screening and prenatal diagnosis among the British Columbia (Canada) population of Chinese descent
Authors: Yong Karina N , Wadsworth Louis D , Langlois Sylvie , Yong Siu Li , Wilson R Douglas
Published: March 2003

The goal of thalassemia screening is the identification, prior to the conception or birth of an affected child, of couples where both partners are thalassemia carriers. When both partners are identified as carriers for alpha‐ or beta‐thalassemia, the risk of having a fetus who is homozygous or compound heterozygous for the abnormal gene is 25%. A study was performed to identify whether routine screening for thalassemia is indicated for the Chinese population in British Columbia (BC). In a population of 783 subjects, studied either prospectively or retrospectively, 5.0% were alpha‐thalassemia carriers and 1.7% were beta‐thalassemia carriers.In addition, a review of all BC cases of prenatal diagnosis for thalassemia over a 6‐year period indicated that 26% of couples were identified as alpha‐thalassemia carriers because of a second or third trimester diagnosis of fetal hydrops, and 17% of couples referred for beta‐thalassemia already had an affected child. The experience with prenatal diagnosis shows that a significant proportion of at‐risk couples are not identified prior to or early in a pregnancy. The prevalence of carriers for thalassemia would warrant a program of education and routine screening for this condition in the BC Asian population.
Nevoid basal cell carcinoma syndrome. Clinical findings in 37 Italian affected individuals
Authors: Lo Muzio Lorenzo , Nocini Pier Francesco , Savoia Anna , Consolo Ugo , Procaccini Maurizio , Zelante Leopoldo , Pannone Giuseppe , Bucci Paolo , Dolci Marco , Bambini Fabrizio , Solda Paola , Favia Gianfranco
Published: March 2003

Nevoid basal cell carcinoma syndrome (NBCCS) is a hereditary condition transmitted as an autosomal dominant trait with complete penetrance and variable expressivity. The syndrome is characterised by numerous basal cell carcinomas (BCCs), odontogenic keratocysts of the jaws, palmar and/or plantar pits, skeletal abnormalities and intracranial calcifications.In this paper, the clinical features of 37 Italian patients are reviewed. Jaw cysts and calcification of falx cerebri were the most frequently observed anomalies, followed by BCCs and palmar/plantar pits. Similar to the case of African–Americans, the relatively low frequency of BCCs in the Italian population is probably due to protective skin pigmentation. A future search based on mutation screening might establish a possible genotype–phenotype correlation in Italian patients.
Missense mutations in phosphomannomutase 2 gene in two Japanese families with carbohydrate‐deficient glycoprotein syndrome type 1
Authors: Kondo I , Mizugishi K , Yoneda Y , Hashimoto T , Kuwajima K , Yuasa I , Shigemoto K , Kuroda Y
Published: March 2003

Carbohydrate‐deficient glycoprotein syndrome type 1 (CDG1) (MIM: 212065) is an autosomal recessive disorder with psychomotor retardation, strokelike episodes, ataxia, and olivopontocerebellar atrophy (OPCA) of neonatal onset. Recently, DNA substitutions in a gene for phosphomannomutase 2 (PMM2), mapped to 16p13, were identified in patients with CDG1. Biochemical findings in previously reported Japanese patients with CDG1 were slightly different from those of Caucasians, suggesting genetic heterogeneity of CDG1 in Japanese patients. We investigated the DNA sequence of PMM2 in two unrelated Japanese families with CDG1. Missense mutations in exon 5 (Phe144Leu) and exon 8 (Tyr229Ser, Arg238Pro) of the PMM2 gene were present in two families, but they were not present in 72 unrelated healthy Japanese individuals. One of the missense mutations, Phe144Leu in exon 5, was common to two families with CDG1. Our findings confirm that mutations in the PMM2 gene account for at least some Japanese patients with CDG1 similar to that seen in Caucasians and that exons 5 and 8 are hot spots of mutations of CDG1 caused by the PMM2 gene.
High frequency of de novo deletions in Mexican Duchenne and Becker muscular dystrophy patients. Implications for genetic counseling
Authors: Alcántara Ma , Villarreal Mt , Del Castillo V , Gutiérrez G , Saldaña Y , Maulen I , Lee R , Macías M , Orozco L
Published: March 2003

Duchenne muscular dystrophy (DMD) is the most common lethal hereditary neuromuscular disease. As there is no effective treatment, accurate carrier detection is essential for genetic counseling and prevention. Although linkage analysis has been widely used for this purpose, being an indirect analysis it has several limitations. Using linkage analysis for carrier detection, we found serious limitations, mainly because 82.9% of all proposita were isolated cases. We used quantitative polymerase chain reaction for direct carrier detection in families with exon deletions and found a higher than expected frequency of de novo deletions (62.2%). Furthermore, only 20.7% of the mothers of isolated deletion DMD/Becker muscular dystrophy (BMD) patients were found to be carriers. This result suggests that the Mexican population has a high frequency of de novo DMD mutations.
Chromosome 11q13 and atopic asthma
Authors: Adra C N , Mao X‐Q , Kawada H , Gao P‐S , Korzycka B , Donate J L , Shaldon S R , Coull P , Dubowitz M , Enomoto T , Ozawa A , Syed S A , Horiuchi T , Khaeraja R , Khan R , Lin S R , Flinter F , Beales P , Hagihara A , Inoko H , Shirakawa T , Hopkin Jm
Published: March 2003

Asthma is a complex syndrome in which bronchial inflammation and smooth muscle hyperactivity lead to labile airflow obstruction. The commonest form of asthma is that due to atopy, which is an immune disorder where production of IgE to inhaled antigens leads to bronchial mucosal inflammation. The ultimate origins of asthma are interactive environmental and genetic factors. The genetics is acknowledged to be heterogeneous, and one chromosomal region of interest and controversy has been 11q13. To clarify the nature of the chromosome 11q13 effect in atopy and asthma, we conducted a genetic association study in subjects with marked atopic asthma and matched controls, which incorporated the study of 13 genetic variants over a distance of 10–12 cM and which took account of detailed immune and clinical phenotyping. Association with high IgE levels was limited to the interval flanked by D11S1335 and CD20 in a 0.8‐Mb interval and was greatest for variants of FcɛRIβ and HTm4; these variants also associated with asthma (recurrent wheeze with labile airflow obstruction and need for regular inhaler treatment). At the more telomeric marker, D11S480, variants associated with asthma, but not with high IgE levels. The data might support the possibility of multiple loci relevant to atopic asthma on chromosome 11q13.
Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency
Authors: Al‐Jishi E , Meyer Bf , Rashed Ms , Al‐Essa M , Al‐Hamed Mh , Sakati N , Sanjad S , Ozand Pt , Kambouris M
Published: March 2003

Pyroglutamic aciduria (5‐oxoprolinuria) is a rare autosomal recessive disorder caused by either glutathione synthetase deficiency (GSSD) or 5‐oxoprolinase deficiency. GSSD results in low glutathione levels in erythrocytes and may present with hemolytic anemia alone or together with pyroglutamic aciduria, metabolic acidosis, and CNS damage. Five patients with pyroglutamic aciduria were studied. All presented with hemolytic anemia and metabolic acidosis. Two (brothers) also had Fanconi nephropathy, which is not seen in pyroglutamic aciduria. Molecular analyses of the GSS gene was performed in 3 patients. RT‐PCR and heteroduplex analysis identified a homozygous deletion in 1 patient and a homozygous mutation in 2 others (brothers with Fanconi nephropathy). Sequencing of glutathione synthetase (GSS) cDNA from the first patient showed a 141‐bp deletion corresponding to the entire exon 4, whilst the corresponding genomic DNA showed a G491→A homozygous splice site mutation. Sequencing of GSS cDNA from the Fanconi nephropathy patients showed a C847→T [ARG283→CYS] mutation in exon 9.
A de novo complex chromosomal rearrangement with nine breakpoints characterised by FISH in a boy with mild mental retardation, developmental delay, short stature and microcephaly
Authors: Joyce Christine A , Cabral de Almeida José Carlos , Santa Rose Antonio Abílio , Correia Patricia , Moraes Lúcia , Bastos Elenice , Llerena Jr Juan
Published: March 2003

A de novo complex chromosome rearrangement (CCR) involving chromosomes 1, 6, 7, 15 and Y was detected in a boy with mental retardation, short stature, and microcephaly. Fluorescence in situ hybridisation (FISH) with whole chromosome painting libraries, band‐specific cosmids and telomeric probes was essential for the characterisation of the rearrangement. The CCR was shown to be the result of at least nine chromosomal breaks and involved the alternating insertion of two segments of the short arm of chromosome 1 and two segments of the long arm of chromosome 6 into a novel derived chromosome 7. A non‐reciprocal translocation between the distal short arm of the same chromosome 7 and the distal long arm of the Y chromosome was also found, together with a paracentric inversion of the long arm of chromosome 15. The only detectable imbalance was a deletion of the heterochromatic Yq telomeric region. FISH investigations in this case have revealed an additional complexity in this CCR, which has implications for reproductive risk assessment and genetic counselling.
Three common CFTR mutations should be included in a neonatal screening programme for cystic fibrosis in Sweden
Authors: Schaedel C , Hjelte L , De Monestrol I , Johannesson M , Kollberg H , Kornfält R , Holmberg L
Published: March 2003

Children with cystic fibrosis (CF) diagnosed by neonatal screening have a better nutritional development and other advantages compared with those in a nonscreened group. The two‐tier immunoreactive trypsinogen (IRT)/DNA screening protocol has been found superior to the single‐tier IRT approach, improving the positive predictive value and thus reducing the false–positive rate. However, variations of the DNA test are required for different populations. In this study we examined CFTR (cystic fibrosis transmembrane conductance regulator) mutations in 331 CF patients attending the centres in Stockholm, Lund and Uppsala, comprising about 75% of the CF population in Sweden. The frequency of ΔF508 among CF alleles was 68.3% There were two other mutations, 394delTT and 3659delC, found to be fairly frequent, amounting to 8.5 and 7.9%, respectively. Other mutations were comparatively rare. A simple and effective method of analysing the three mutations from Guthrie cards has been developed. Assuming Hardy–Weinberg equilibrium, 90% of our CF patients will be expected to carry at least one ΔF508 allele and 97.6% to carry at least one ΔF508, 394delTT or 3659delC copy. Including the latter two in a screening programme would thus substantially reduce the risk of a false–negative outcome.
Human renin gene BglI dimorphism associated with hypertension in two independent populations
Authors: Frossard Philippe M , Lestringant Gilles G , Malloy Mary J , Kane John P
Published: March 2003

The renin (REN) gene is a good candidate that could underlie an individual's genetic susceptibility to human essential hypertension (EHT). We describe here a polymerase chain reaction‐based assay for detection of a BglI dimorphic site located in the first intron of the REN gene. In this retrospective, case–control, association study, we investigated BglI allele and genotype distributions in 554 subjects (280 hypertensives and 274 normotensives) from the United Arab Emirates (UAE) – a genetically homogeneous ethnic population with no history of smoking or alcohol consumption – and in 485 hypercholesterolemic, US Caucasian subjects (250 hypertensives and 235 normotensives). A statistically significant association was found between alleles on which the BglI site is present [BglI(+)] and clinical diagnosis of EHT in the UAE sample group (odds ratio=2.69, p=0.0006), and a similar trend was observed in the US group (odds ratio=1.97, p=0.01). BglI(+) homozygous status was also investigated in the US group and found to be associated with elevated systolic and diastolic blood pressure values (respectively, 144.8±26.1 vs. 134.1±23.0 mmHg, p=0.04; and 91.0±12.5 vs. 82.2±12.7 mmHg, p=0.009).In conclusion, variations of the REN (or of a nearby) gene that may be in linkage disequilibrium with the RENBglI(+) marker could play a role in contributing to an increased individual's genetic susceptibility to EHT in the UAE population and amongst US hypercholesterolemic Caucasians. Such a genetic influence, which seems to show a recessive mode of inheritance, could also be implicated in raising both systolic and diastolic blood pressures.
Perceptions of the outcome of orthopedic surgery in patients with chondrodysplasias
Authors: Hunter Alasdair Gw
Published: March 2003

As part of a larger survey of patients with chondrodysplasias, 197 patients or their parents were asked whether they had undergone orthopedic surgery related to their chondrodysplasia and, if so, to rate their impression of the outcome. Seventy‐four patients (37.6%) had undergone a total of 152 procedures (221 if concurrent bilateral operations are counted separately). The percentage of patients treated surgically ranged from a low of 8.3% for hypochondroplasia to a high of 87.5% for diastrophic dysplasia. Of the patients who had surgery, the mean number of procedures per patient ranged from 1.0 for hypochondroplasia to 2.69 for pseudoachondroplasia. Of 180 individual procedures related to the limbs, the outcome in 88.8% was judged ‘a bit better’ or higher and in 68.8% ‘much better’ or higher. The responses ranged from a low of 70.4 and 66.7%, respectively for proximal femoral osteotomies to a high of 100 and 85.9% for hip replacement. The comparable figures for spine related surgery were 81.8 and 48.5% with a low of 58.3 and 50.0% for foramen magnum–cervical surgery and a high of 93.8 and 43.8% for thoracolumbar procedures. The expressed perception of lack of satisfaction varied not only by procedure but by diagnosis. Overall, patients perceived a high level of post‐surgical improvement, although a number experienced subsequent deterioration and the need for further intervention.
Prevalence of human leukocyte antigen DQA1 and DQB1 alleles in Kuwaiti Arab children with type 1 diabetes mellitus
Authors: Haider Mz , Shaltout A , Alsaeid K , Qabazard M , Dorman J
Published: March 2003

The prevalence of human leukocyte antigen (HLA) DQB1 and DQA1 alleles has been determined in 78 Kuwaiti Arab children with insulin‐dependent diabetes mellitus (IDDM) and in 57 normal healthy controls with similar ethnic background. The typing of HLA‐DQ alleles was carried out using an allele‐specific DNA‐based polymerase chain reaction (PCR) SSP method. DR typing was also performed in 212 control subjects using PCR‐SSP (sequence specific primer) method. A significantly higher frequency of DQB1*0201 allele was found in IDDM cases compared to the controls (p<0.001). There was no significant difference in the prevalence of DQB1 alleles *0302, *0501, and *0602 between IDDM cases and the controls. In contrast, DQB1 alleles *0301, *0402, *0502, *0602, and *0603 were represented at a somewhat higher frequency in controls compared to the IDDM cohort. The frequency of DQA1 allele *0301, which encode for an Arg at codon 52, was significantly higher in the IDDM patients compared to the controls (p<0.001). The frequency of DQA1 allele *0302 was also higher in IDDM cases than controls (p=0.034) but the difference was less pronounced than DQA1*0301. Amongst the Arg52 alleles, no significant difference was detected in the frequency of *0401 between IDDM cases and the controls and the allele *0501 was detected only in controls. For non‐Arg52 alleles *0103, *0104, and *0201, the differences in the two groups were not significant, with the exception of allele *0104 (p=0.024). DR3 was the most common type in the Kuwaiti general population (28%) and DRB1*0301 was detected in 41% of the individuals with DR3 specificity. Analysis of HLA‐DQB1/DQA1 haplotypes from IDDM cases and controls revealed a significantly high frequency of haplotype DQA1*0301/DQB1*0201 between Kuwaiti IDDM cases (49/78, 63%) and the controls (8/57, 14%).
An SRY‐negative XX male with Huriez syndrome
Authors: Vernole Patrizia , Terrinoni Alessandro , Didona Biagio , De Laurenzi Vincenzo , Rossi Pellegrino , Melino Gerry , Grimaldi Paola
Published: March 2003

This report studies a 42‐year‐old 46,XX patient affected by palmoplantar keratoderma, clinically classified as Huriez syndrome. The patient showed a male phenotype with apparently normal male features including testicular development. Cytogenetic and chromosomal painting analysis excluded the presence of translocation of the Y chromosome. PCR analysis of genomic DNA failed to detect the presence of the testis‐determining gene, SRY. The presence of other Y‐chromosome genes, known to be involved in testicular maturation and spermatogenesis, has also been analyzed. The data suggest that the sex reversal in this 46,XX male patient is due to a defect on a yet unidentified autosomal or X‐linked sex‐determining gene. The relationship between the sex reversion and the presence of sclerotylosis is discussed.
The genetics of osteoporosis: ‘complexities and difficulties’
Authors: Giguère Yves , Rousseau François
Published: March 2003

Osteoporosis is characterized by a decrease in bone mass as well as a deterioration of the bone architecture resulting in an increased risk of fracture. Although the disease is multifactorial, twin studies have shown that genetic factors account for up to 80% of the variance in bone mineral density, the best known predictor of the risk of osteoporosis. Some loci, such as the vitamin D and estrogen receptor genes, as well as the collagen type Iα1 locus, are promising genetic determinants of bone mass, and possibly other bone phenotypes, but this is controversial and the molecular basis of osteoporosis remains largely undefined. Considering that the effect of each candidate gene is expected to be modest, discrepancies between allelic association studies may have arisen because different populations carry different genetic backgrounds and exposure to environmental factors. Also, we realize the importance of gene–gene as well as gene–environment interactions as significant determinants of bone density and risk of osteoporosis. The use of new tools such as small nucleotide polymorphism maps now allows the possibility to perform allelic association studies in the context of whole‐genome search. However, specific study design strategies in large epidemiological studies as well as the best statistical approach will need to be established. We may expect the development of population‐specific at‐risk profiles for osteoporosis that would include genetic and environmental factors, as well as their interactions. This should eventually lead to better prevention strategies and more adapted therapies against osteoporosis.
A pilot study of the possible role of familial defects in anticoagulation as a cause for terminal limb reduction malformations
Authors: Hunter Alasdair GW
Published: March 2003

Terminal limb deficiency defects affect between three and eight babies per 10 000 births and are an important cause of disability. Established causes for these malformations include single gene disorders, chromosome abnormalities, teratogens, and amniotic bands. However, the etiology remains unknown in a significant proportion of cases. Several authors have hypothesized that vascular accidents, either bleeds or vessel occlusions, may underlie a substantial number of cases; but, for the most part, the origin of such events remains obscure. Over the past several years, an increasing number of genetic thrombophilias have been recognized and have been associated with increased risks of peri‐ and post‐natal occlusive disease, and with higher rates of recurrent pregnancy loss. The hypothesis to be examined in this pilot study was whether the inherited thrombophilias might be associated with a vascular cause of some terminal limb deficiency defects. Towards that end, protein C, protein S, antithrombin III, factor V Leiden mutation, prothrombin (G20210A) variant, methylenetetrahydrofolate reductase variant, plasma homocysteine, anticardiolipin IgM and IgG antibodies, and lipoprotein (a) were measured in 24 mother–child pairs in which the child had a terminal limb defect. The results provided some evidence that there may be an excess of thrombophilias present in such families and that they may play some etiological role in a subset of these types of limb malformations.
Identification of four novel mutations of the low‐density lipoprotein receptor gene in Korean patients with familial hypercholesterolemia
Authors: Shin Jin A , Han Kim Sung , Kyung Kim Un , Jin Chae Jae , Joon Choe Seong , Namkoong Yong , Soo Kim Hyo , Bae Park Young , Choo Lee Chung
Published: March 2003

To obtain insight into the genetic variation of the low‐density lipoprotein (LDL) receptor gene in Korean patients with familial hypercholesterolemia (FH), we used single‐strand conformation polymorphism to screen all 18 exons and a promotor of the LDL receptor gene in 20 unrelated Korean FH patients. Four novel point mutations were detected in 5 FH patients and were characterized by sequence analysis. Of them, one is a nonsense mutation, a Glu→Stop (C AG→T AG) at codon 161, and results in a large deletion. The other three, which were a Ala→Glu (GC G→GĀG) mutation at signal peptide, Cys→Tyr (TG C→TĀC) at codon 210, and Pro→Leu (CT G→CC G) at codon 584, were novel missense mutations, which modified the highly conserved region of the LDL receptor gene. All these mutations were absent in normolipidemic controls and were associated in heterozygote carriers with clinical signs of FH. Identification of these novel mutations provides another example of the molecular heterogeneity of the LDL receptor gene mutations causing FH.
Somatic segregation errors predominantly contribute to the gain or loss of a paternal chromosome leading to uniparental disomy for chromosome 15
Authors: Robinson Wendy P. , Christian Susan L. , Kuchinka Brian D. , Peñaherrera Maria S. , Das Soma , Schuffenhauer Simone , Malcolm Susan , Schinzel Albert A. , Hassold Terry J. , Ledbetter David H.
Published: March 2003

Paternal uniparental disomy (UPD) for chromosome 15 (UPD15), which is found in ∼2% of Angelman syndrome (AS) patients, is much less frequent than maternal UPD15, which is found in 25% of Prader–Willi syndrome patients. Such a difference cannot be easily accounted for if ‘gamete complementation’ is the main mechanism leading to UPD. If we assume that non‐disjunction of chromosome 15 in male meiosis is relatively rare, then the gain or loss of the paternal chromosome involved in paternal and maternal UPD15, respectively, may be more likely to result from a post‐zygotic rather than a meiotic event. To test this hypothesis, the origin of the extra chromosome 15 was determined in 21 AS patients with paternal UPD15 with a paternal origin of the trisomy. Only 4 of 21 paternal UPD15 cases could be clearly attributed to a meiotic error. Furthermore, significant non‐random X‐chromosome inactivation (XCI) observed in maternal UPD15 patients (p<0.001) provides indirect evidence that a post‐zygotic error is also typically involved in loss of the paternal chromosome. The mean maternal and paternal ages of 33.4 and 39.4 years, respectively, for paternal UPD15 cases are increased as compared with normal controls. This may be simply the consequence of an age association with maternal non‐disjunction leading to nullisomy for chromosome 15 in the oocyte, although the higher paternal age in paternal UPD15 as compared with maternal UPD15 cases is suggestive that paternal age may also play a role in the origin of paternal UPD15.
Neural stem cells – a versatile tool for cell replacement and gene therapy in the central nervous system
Authors: Ourednik V , Ourednik J , Park KI , Snyder EY
Published: March 2003

In recent years, it has become evident that the developing and even the adult mammalian central nervous system contains a population of undifferentiated, multipotent cell precursors, neural stem cells, the plastic properties of which might be of advantage for the design of more effective therapies for many neurological diseases. This article reviews the recent progress in establishing rodent and human clonal neural stem cell lines, their biological properties, and how these cells can be utilized to a correct variety of defects, with prospects for the near future to harness their behaviour for neural stem cell‐based treatment of diseases in humans.
Sisters homozygous for the spinocerebellar ataxia type 6 (SCA6)/CACNA1A gene associated with different clinical phenotypes
Authors: Kato Takeshi , Tanaka Fumiaki , Yamamoto Masahiko , Yosida Eiji , Indo Toshikatsu , Watanabe Hidetaka , Yoshiwara Tsuyoshi , Doyu Manabu , Sobue Gen
Published: March 2003

Spinocerebellar ataxia type 6 (SCA6) is a neurodegenerative disease caused by a CAG repeat expansion in the CACNA1A gene. The neurodegeneration that occurs in CAG repeat diseases is considered to share a common mechanism that may result in the gain of a toxic function related to the expanded polyglutamine tracts. However, the phenotypic expression in homozygotes for CAG repeat diseases has been controversial, and is not clearly related to a gain of functional mechanism. We identified a Japanese family with two sisters who were homozygous for the SCA6 with identical CAG repeat expansion (25/25). They showed an earlier age of onset (27 years in both) than their father (44 years), a heterozygote with an expanded allele showing the same CAG repeat length as the homozygotes (25/14). Interestingly, the two sisters showed differences in disease progression and severity, although the age of onset and CAG repeat length were identical. These findings strongly suggest that the gene dosage influences the age of onset, but other unknown factors are also important in the phenotypic expression of homozygous SCA6.
Chronic myelomonocytic leukaemia in a child with constitutional partial trisomy 8 mosaicism
Authors: Brady Af , Waters Cs , Pocha Mj , Brueton La
Published: March 2003

We present a 3‐year‐old boy with constitutional partial trisomy 8 mosaicism (karyotype 47,XY,+del(8)(p12)/46,XY) who developed chronic myelomonocytic leukaemia and we review the few reported cases of constitutional trisomy 8 mosaicism (CT8M) associated with malignancy. This case highlights the association between CT8M and the development of malignancies, haematological malignancies in particular.
Insights into the pathogenesis of neurofibromatosis 1 vasculopathy
Authors: Hamilton SJ , Friedman JM
Published: March 2003

Intrinsic lesions of arterial walls are an important manifestation of neurofibromatosis 1 (NF1). Neurofibromin is expressed in blood vessel endothelial and smooth muscle cells, and NF1 vasculopathy may result from an alteration of neurofibromin function in these cells. Elucidation of the role of neurofibromin in the maintenance and repair of blood vessels may lead to novel approaches to the treatment of NF1 vasculopathy and vascular disease in general.
Prevalence of CFTR mutations in hypertrypsinaemia detected through neonatal screening for cystic fibrosis
Authors: Scotet V. , De Braekeleer M. , Audrézet M.‐P. , Lodé L. , Verlingue C. , Quéré I. , Mercier B. , Duguépéroux I. , Codet J.‐P. , Moineau M.‐P. , Parent P. , Férec C.
Published: March 2003

Nowadays, most of the neonatal screening programs for cystic fibrosis (CF) combine the assay of immunoreactive trypsinogen (IRT) with the analysis of the most common mutations of the CFTR gene. The efficiency of this strategy is now well established, but the identification of heterozygotes among neonates with increased IRT is perceived as a drawback. We proposed to assess the heterozygosity frequency among the children with hypertrypsinaemia detected through the CF screening program implemented in Brittany (France) 10 years ago, to describe the CFTR mutations detected in them and to determine the frequency of the IVS8‐5T variant. The molecular analysis relies, in our protocol, on the systematic analysis of three exons of the gene (7‐10‐11). A total of 160 019 babies were screened for CF in western Brittany between 1992 and 1998. Of the 1 964 newborns with increased IRT (1.2%), 60 were CF and 213 were carriers. Heterozygosity frequency was 12.8%, i.e. 3 times greater than in the general population (3.9%; p<10−6). Variability of mutations detected in carriers was greater than in CF children (21 mutations versus 10) and a high proportion of mild mutations or variants (A349V, R297Q, R347H, V317A, G544S, R553G, etc) was observed in carriers. The allelic frequency of the 5T (5.6%) was not significantly increased in this cohort. This study is consistent with previous ones in finding a significantly higher rate of heterozygotes than expected among neonates with hypertrypsinaemia. The strategy of screening used here allows to highlight the variability of mutations detected in heterozygotes and to show that severe mutations, as well as mild mutations, have been observed in neonates with hypertrypsinaemia. If there is no doubt that neonatal hypertrypsinaemia is associated with an elevated frequency of carriers, the underlying mechanisms remain obscure.
Relation of cardiac abnormalities and CTG‐repeat size in myotonic dystrophy
Authors: Finsterer J , Gharehbaghi‐Schnell E , Stöllberger C , Fheodoroff K , Seiser A
Published: March 2003

It is unclear if the severity of cardiac involvement in patients with myotonic dystrophy (MD) is related to the size of the CTG‐repeat expansion. This open, uncontrolled, observational, prospective study aimed to find out if there is a relation between the severity of cardiac involvement in MD and the CTG‐repeat size. In 21 patients with MD, (8 women, 13 men, aged 11–88 years) a detailed cardiologic examination, including history, clinical examination, electrocardiography (ECG), transthoracic echocardiography and ambulatory 24‐h ECG, was carried out and cardiac involvement was assessed according to a previously described scoring system. Additionally, the CTG‐repeat size was determined from nuclear DNA of blood leukocytes.  The correlation between the CTG‐repeat size and the mean heart rate, PQ‐interval, QTc‐interval, fractional shortening, left ventricular enddiastolic diameter, septal thickness, posterior wall thickness, mean heart rate on 24‐h ECG and cardiac involvement score was r=0.47, r=0.086, r=0.11, r=−0.27, r=−0.34, r=−0.06, r=−0.12, r=0.16 and r=0.09 (all p>0.05), respectively. In patients 21–30, 31–40 and 41–50 years of age, cardiac involvement increased with increasing CTG‐repeat size. In younger patients, the number of CTG‐repeats needed to develop a reasonable cardiac involvement was higher than in older patients. Depending on age, cardiac involvement increases with increasing CTG‐repeat size obtained from blood leukocytes in patients with MD.
The developmental program of the hypothalamus and its disorders
Authors: Michaud JL
Published: March 2003

The hypothalamus integrates physiological processes essential for survival and reproduction. Recent studies have shown that developmental events can affect these processes. Pathways required for the induction of the ventral midline of the hypothalamus or for the differentiation of specific hypothalamic lineages have the potential of causing endocrine and metabolic disorders, including obesity. Also, some genes with paternal monoallelic expression are involved in the development of hypothalamic centers that are critical physiological regulators. Developmental defects affecting the hypothalamus might represent a more frequent cause of clinical disorders than previously suspected.
Association of a single nucleotide polymorphism in CPB2 encoding the thrombin‐activable fibrinolysis inhibitor (TAFI) with blood pressure
Authors: Koschinsky ML , Boffa MB , Nesheim ME , Zinman B , Hanley AJG , Harris SB , Cao H , Hegele RA
Published: March 2003

Thrombin‐activable fibrinolysis inhibitor (TAFI) is a hepatically secreted zymogen, whose substrates include bradykinin. The CPB2 gene encoding TAFI is a candidate gene for blood pressure. A recently identified single nucleotide polymorphism (SNP) in the CPB2 coding region, designated as 1057C>T, results in an amino acid change at TAFI residue 325 (Ile>Thr325). We found that the genotype based on this SNP was significantly associated with blood pressure in aboriginal Canadians. Specifically, analysis of variance showed that homozygotes for CPB2 1057T had significantly lower diastolic blood pressure than subjects with other CPB2 genotypes. CPB2 genotype accounted for ∼3% of the total variation in diastolic blood pressure, consistent with the expected magnitude of a modest genetic effect in a complex trait such as blood pressure. Although the mechanism underlying the association is unclear, the findings are of interest because TAFI may provide a link between coagulation and blood pressure regulation.