bluuebunny/crossref_metadata_2025 huggingface dataset:
The link between allergic rhinitis and allergic asthma: A prospective population‐based study. The Copenhagen Allergy Study
Authors: Linneberg A. , Henrik Nielsen N. , Frølund L. , Madsen F. , Dirksen A. , Jørgensen T.
Published: March 2003

Background: It has been hypothesized that allergic rhinitis and allergic asthma are manifestations of the same disease entity. We aimed to investigate the relationship between allergic rhinitis and allergic asthma.

Methods: Participants in a population‐based study of 15–69‐year‐olds in 1990 were invited to a follow‐up in 1998. A total of 734 subjects were examined on two occasions eight years apart. Allergic rhinitis to pollen was defined as a history of nasal symptoms on exposure to pollens and IgE specific to pollen. Allergic asthma to pollen was defined as a history of lower airway symptoms on exposure to pollens and IgE specific to pollen. Similarly, diagnoses of allergic rhinitis and allergic asthma to animals or mite were defined.

Results: At follow‐up, all subjects with allergic asthma to pollen (n = 52) had in addition allergic rhinitis to pollen. In the longitudinal analysis, there were a total of 28 new (incident) cases of allergic asthma to pollen. They all had allergic rhinitis to pollen at baseline, or had developed allergic rhinitis to pollen at follow‐up. Accordingly, allergic rhinitis to animals and mite were ubiquitous in subjects with allergic asthma to animals and mite, respectively.

Conclusions: The results support the hypothesis that allergic rhinitis and allergic asthma are manifestations of the same disease entity.
Increased eosinophil transmigration after nasal allergen challenge in children with allergic asthma and rhinitis
Authors: Lönnkvist K. , Moshfegh A. , Pedroletti C. , Hedlin G. , Halldén G. , Lundahl J.
Published: March 2003

Background: Eotaxin and interleukin‐5 together provide the signal essential for eosinophil transmigration to airway tissue in allergic reactions. However, it is not known whether peripheral blood eosinophils (PBE) possess an increased transmigration capacity in vitro after allergen challenge in vivo before they leave the circulation. We aimed to determine whether PBE in cat‐sensitized children have increased spontaneous and/or eotaxin‐induced transmigration capacity in vitro, and to what extent allergen challenge alters this feature.

Methods: Fourteen cat‐allergic children and four healthy controls underwent nasal challenge with cat‐allergen. Blood samples were drawn prechallenge and at 2 h and 24 h postchallenge. We analyzed the in vitro transmigration of PBE, with and without eotaxin as a chemoattractant. We used a transmigration assay with fibronectin‐coated membranes. Eosinophil cationic protein (ECP) and PBE counts were run in parallel.

Results: The spontaneous transmigration capacity of eosinophils in vitro was significantly higher at 2 h after allergen challenge (P < 0.01 vs. prechallenge) and returned to prechallenge levels at 24 h postchallenge (P < 0.02 vs. 2 h postchallenge). Addition of eotaxin further augmented the increased transmigration. In concordance, no accompanying changes were measured in the levels of eosinophils in blood or ECP in serum. Furthermore no spontaneous or eotaxin‐induced eosinophil transmigration was detected in healthy controls.

Conclusion: PBE possess increased spontaneous (and eotaxin‐induced) capacity to transmigrate as early as 2 h after allergen challenge in allergic children, without accompanying signs of eosinophil activation in terms of increased PBE count or ECP level. This is probably due to the increased stage of activation of the eosinophil, often referred to as “priming”.
Decreased levels of coenzyme Q10 in patients with bronchial asthma
Authors: Gazdík F. , Gvozdjáková A. , Nádvorníková R. , Repická L. , Jahnová E. , Kucharská J. , Piják M. R. , Gazdíková K.
Published: March 2003

Background: The contribution of free oxygen radicals in the pathogenesis of bronchial asthma is generally accepted. The modulation of antioxidative defence by supplementation with antioxidants represents additive therapy in complex management of disease. The aim of the study was to assess the levels of coenzyme Q10, α‐tocopherol, and β‐carotene both in plasma and whole blood, and malondialdehyde (MDA) and eosinophil cationic protein (ECP) in plasma of asthmatics (As).

Methods: Fifty‐six As (15 males and 41 females) aged from 19 to 72 years (mean age 46 years) suffering from allergic asthma were enrolled into the study. The control group comprised 25 healthy volunteers (16 males, 9 females) aged 25–50 years.

Results: The concentrations of CoQ10 decreased significantly both in plasma and whole blood, compared with healthy volunteers (0.34 ± 0.15 μmol/l vs. 0.52 ± 0.15 μmol/l, 0.33 ± 0.14 μmol/l vs. 0.50 ± 0.13 μmol/l, P < 0.001, P< 0.001, respectively). The levels of α‐tocopherol were decreased both in plasma and whole blood in comparison with controls [24.10 μmol/l (19.8; 30.5), vs. 33.20 μmol/l (28.25; 38.05), 17.22 ± 6.45 μmol/l vs. 21.58 ± 7.92 μmol/l, P= 0.006, P = 0.01, respectively]. The levels of MDA were elevated over the reference range in both groups (reference range < 4.5 μmol/l). No changes were seen in β‐carotene concentrations. Positive correlation was found between whole blood CoQ10 and α‐tocopherol concentrations.

Conclusion: Results of the study suggest a possible contribution of suboptimal concentrations of CoQ10 on antioxidative dysbalance in As and provide a rationale for its supplementation.
Environmental urban factors (air pollution and allergens) and the rising trends in allergic respiratory diseases
Authors: D'Amato G.
Published: March 2003

Respiratory allergic diseases such as rhinitis and bronchial asthma appear to be increasing worldwide, affecting in particular subjects living in urban areas, and the reasons for this increase are still largely unknown. Although the role played by air pollution has yet to be clarified, a body of evidence suggests that urbanization, with its high levels of vehicle emissions and a westernised lifestyle are linked to the rising frequency of these diseases observed in most industrialized countries. Laboratory studies confirm the epidemiological evidence that inhalation of some pollutants, either individually or in combination, adversely affect lung function in asthmatics. Air pollutants may not only increase the frequency and intensity of symptoms in already allergic patients but may promote airway sensitization to airborne allergens in predisposed subjects. By attaching to the surface of pollen grains and of plant‐derived paucimicronic particles, pollutants can modify the morphology of these antigen‐carrying agents and alter their allergenic potential. In addition, by inducing airway inflammation, pollutants may overcome the mucosal barrier and so ‘prime’ allergen‐induced responses. In other words airway mucosal damage and impaired mucociliary clearance induced by air pollution may facilitate the access of inhaled allergens to the cells of the immune system.
An extra idic(21)(q22.1) in a child with some features of Down’s syndrome
Authors: Gutiérrez‐Angulo M , Ramos Al , Dávalos N , Sánchez‐Corona J , Rivera H
Published: March 2003

A 30‐month‐old boy with mental retardation, hypotonia, joint hyperlaxity, Brushfield spots, open mouth, distal axial triradius t′′, and ulnar loops on both forefingers was found to have a 47,XY,+psu idic(21)(q22.1).ish psu idic(21)(q22.1)(D13Z1/D21Z1++,ETS2−) karyotype. The patient’s phenotype, with only some Down’s syndrome (DS) features, is probably related to his disomy for most or all of the critical region 21q22.2→q22.3 and agrees with the current notion that certain DS features may also result from 21q proximal duplications. The phenotypical comparison with 2 other patients with a similar extra idic(21) reveals some discrepancies, which may be related to the inherent clinical variability of similar imbalances; yet, a real difference between the tetrasomic segments cannot be excluded. Noticeably, all 3 patients with 21q proximal tetrasomy did not have cardiac defect and exhibited none or just one out of the five other DS phenotypic features attributed to a single gene or cluster on distal 21q22.
Procedure to protect confidentiality of familial data in community genetics and genomic research
Authors: Gaudet Daniel , Arsenault Steve , Bélanger Céline , Hudson Thomas , Perron Patrice , Bernard Manon , Hamet Pavel
Published: March 2003

The collection of familial data is an essential step for community genetics programs or genetic research. Ethical issues concerning privacy and confidentiality present a major challenge in such programs. In order to keep familial data confidential, we have developed a family‐based numerical coding procedure which allows the use of confidential data and the determination of familial relationships without risk of disclosure. This procedure is composed of two parts: the physical separation of identifying information and individual data; and the use of a code containing all the information required to build family trees. This procedure has been used in Eastern Quebec since 1995, mainly for screening, genetic counseling, research on familial dyslipidemias, public health intervention, and research projects on the genetics of complex traits, such as arterial hypertension and coronary artery disease.
Partial DiGeorge syndrome in two patients with a 10p rearrangement
Authors: Van Esch Hilde , Groenen Peter , Daw Sarah , Poffyn Ann , Holvoet Maureen , Scambler Peter , Fryns Jean‐Pierre , Van de Ven Wim , Devriendt Koen
Published: March 2003

We describe 2 patients with a partial DiGeorge syndrome (facial dysmorphism, hypoparathyroidism, renal agenesis, mental retardation) and a rearrangement of chromosome 10p. The first patient carries a complex chromosomal rearrangement, with a reciprocal insertional translocation between the short arm of chromosome 10 and the long arm of chromosome 8, with karyotype 46, XY ins(8;10) (8pter→8q13::10p15→10p14::8q24.1→8qter) ins(10;8) (10pter→10p15::8q24.1→8q13::10p14→10qter). The karyotype of the second patient shows a terminal deletion of the short arm of chromosome 10. In both patients, the breakpoints on chromosome 10p reside outside the previously determined DiGeorge critical region II (DGCRII). This is in agreement with previous reports of patients with a terminal deletion of 10p with breakpoints distal to the DGCRII and renal malformations/hypoparathyroidism, and thus adds to evidence that these features may be caused by haploinsufficiency of one or more genes distal to the DGCRII.
Mucopolysaccharidosis type I: Characterization of novel mutations affecting α‐ l‐iduronidase activity
Authors: Lee‐Chen GJ , Lin SP , Tang YF , Chin YW
Published: March 2003

α‐ l‐Iduronidase (IDUA) deficiency (mucopolysaccharidosis type I, MPS I) involves a broad spectrum of clinical severity ranging from a severe Hurler syndrome through an intermediate Hurler–Scheie syndrome to a mild Scheie syndrome. To date, a number of mutations of the IDUA gene are known in Hurler syndrome, but only a few in Hurler–Scheie or Scheie syndrome. The characterization of novel mutations in two patients with the Hurler–Scheie syndrome is reported on. The novel R619G mutation (C–G transversion in codon 619) was apparently homozygous. In transfected COS‐7 cells, R619G caused significant reduction in enzyme activity (1.5% of normal activity), although it did not cause significant reduction in IDUA mRNA or protein level. Conversely, the previously described homozygous T364M mutation (C–T transition in codon 364) caused a decrease in the level of IDUA mRNA. Studies inhibiting RNA synthesis with actinomycin
d or inhibiting protein synthesis with cycloheximide demonstrate that the decrease in the latter mutation is attributable to an increased rate of mRNA decay. By examining the stability of IDUA mRNA and protein, studies provide better insight into the effect of mutation on IDUA activity.
Genetic counselling in multiple sclerosis: risks to sibs and children of affected individuals
Authors: Sadovnick AD , Dircks A , Ebers GC
Published: March 2003

Genetic factors are recognized as having important roles in both the overall etiology and the familial aggregation of multiple sclerosis (MS), leading to increased requests for genetic counselling. This paper is designed to provide familial risk data in a practical format for use during genetic counselling for MS.

Depending on the amount of genetic sharing among family members, the relative risk of MS compared with that for the general population can range from 1 (adopted sibs and children of the MS proband, with whom they share no genetic material) to 190 (monozygotic co‐twins of MS patients, with whom they share 100% of their genetic material). When counselling full sibs of MS patients, risks can be better calculated if information is available on the age of MS onset in the patient and whether or not one parent has MS.
Kabuki syndrome: description of dental findings in 8 patients
Authors: Mhanni AA , Cross HG , Chudley AE
Published: March 2003

The cardinal features of Kabuki (Niikawa–Kuroki) syndrome (KS) include characteristic facial dysmorphic features, mild to moderate mental deficiency, skeletal abnormalities, dermatoglyphic abnormalities, and postnatal growth retardation. We identified 8 patients with KS in a genetics clinic over the past 5 years. All were Caucasians, except for 2 who were of mixed Aboriginal and Caucasian descent. All had the facial gestalt, the dermatoglyphic abnormalities characteristic of the syndrome, and developmental delay. Dental abnormalities of permanent teeth were seen in all 8 cases; 6 had missing lower incisors. Five patients had uniquely abnormal upper incisor teeth shape; the upper incisors had a ‘flat head’ screwdriver‐shaped appearance. Other dental abnormalities included missing lower lateral incisors, missing second premolars, and ectopic upper 6‐year molars. We believe the presence of the unique dental findings will prove useful in the diagnostic assessment of individuals with KS.
Transcervical cells and the prenatal diagnosis of haemoglobin (Hb) mutations
Authors: Cirigliano V , Sherlock J , Petrou M , Ward Rht , Rodeck C , Adinolfi M
Published: March 2003

Prenatal diagnoses of haemoglobin (Hb) mutations were performed using transcervical cells, retrieved by aspiration from the endocervical canal of ten selected pregnant women at about 10 weeks of gestation, prior to chorionic villus sampling (CVS). Both parents were carriers of haemoglobinopaties (thalassaemia or HbS). Clumps of fetal cells were isolated by micromanipulation under an inverted microscope and aliquots of the extracted DNA tested separately for the presence of paternally derived chromosome markers and Hb mutations by quantitative fluorescent polymerase chain reaction (PCR).The correct prenatal diagnosis of Hb diseases, using selected single clumps of trophoblastic cellular elements free of maternal contaminating cells, was achieved in six out of ten cases.
MEFV mutations in multiplex families with familial Mediterranean fever: is a particular genotype necessary for amyloidosis?
Authors: Tekin Mustafa , Yalçinkaya Fatoş , Çakar Nilgün , Akar Nejat , Mısırlıoğlu Müge , Taştan Hakkı , Tümer Necmiye
Published: March 2003

Familial Mediterranean fever (FMF) is an autosomal recessive disease. It is characterized by recurrent febrile episodes in association with peritonitis, pleuritis, and arthritis. Progressive systemic amyloidosis is the most important complication of FMF that inevitably leads to chronic renal failure. Recently, the gene for FMF, MEFV, has been cloned and four missense mutations have been described: M694V, M680I, V726A, and M694I. Initial studies have suggested that the presence of the M694V mutation carries a significant risk for the development of amyloidosis. In this study, we present seven families, in which at least two individuals have been diagnosed with FMF and at least one with amyloidosis. Among 18 individuals, in whom molecular testing was performed for the four aforementioned mutations, ten had amyloidosis. None of these ten individuals was found to be homozygous for the M694V mutation. In three families, there were two sibs with amyloidosis. None of the sib‐pairs with amyloidosis was found to have the same genotype. There were two or more sibs with the same genotype in four families. Only one sib from each family developed amyloidosis in these families. These results provide evidence that FMF patients without the M694V mutation are also at risk for the development of amyloidosis. Particular mutations themselves do not appear to be sufficient to explain the occurrence of amyloidosis in all cases with FMF.
Telomere‐telomere (end to end) fusion of chromosomes 7 and 22 with an interstitial deletion of chromosome 7p11.2→p15.1: phenotypic consequences and possible mechanisms
Authors: Zneimer Susan M , Cotter Philip D , Stewart Sophia D
Published: March 2003

We report a rare case of a de novo end to end fusion of chromosomes 7 and 22 in conjunction with an interstitial deletion of chromosome 7p11.2p15.1 in a newborn with congenital anomalies. The proband presented for chromosome analysis with bilateral cataracts, dysmorphic facies and distal limb abnormalities. Chromosome analysis showed a 45,XY,der(22)psu dic(22;7)(p13;p22.3)del(7)(p11.2p15.1) karyotype. This short arm to short arm fusion of chromosomes 7 and 22 resulted in a pseudodicentric chromosome. The interstitial deletion in the short arm of chromosome 7 was likely a result of breakage and reunion related to instability of the dicentric chromosome. Loss of genetic material in this region of chromosome 7p has been implicated in the pathophysiology of craniosynostosis and cephalopolysyndactyly syndromes.
Polymorphisms of human SP‐A, SP‐B, and SP‐D genes: association of SP‐B Thr131Ile with ARDS
Authors: Lin Z , Pearson C , Chinchilli V , Pietschmann SM , Luo J , Pison U , Floros J
Published: March 2003

An allele association study of 19 polymorphisms in surfactant proteins SP‐A1, SP‐A2, SP‐B, and SP‐D genes in acute respiratory distress syndrome (ARDS) was carried out. Trend‐test analysis revealed differences (p<0.05) in the frequency of alleles for some of the microsatellite markers flanking SP‐B, and for one polymorphism (C/T) at nucleotide 1580 [C/T (1580)], within codon 131 (Thr131Ile) of the SP‐B gene. The latter determines the presence or absence of a potential N‐linked glycosylation site. Multivariate analysis revealed significant differences only for the C/T (1580) polymorphism. When the ARDS population was divided into subgroups, idiopathic (i.e., pneumonia, etc.) or exogenic (i.e., trauma, etc.), significant differences were observed for the C/T (1580), for the idiopathic ARDS group, and the frequency of the C/C genotype was increased in this group. Based on the odds ratio, the C allele may be viewed as a susceptibility factor for ARDS. Although the expression of both C and T alleles occurs in heterozygous individuals, it is currently not known whether these alleles correspond to similar levels of SP‐B protein. These data suggest that SP‐B or a linked gene contributes to susceptibility to ARDS.
Mutational analysis and genotype/phenotype correlation in Turkish Charcot–Marie–Tooth Type 1 and HNPP patients
Authors: Bissar‐Tadmouri N , Parman Y , Boutrand L , Deymeer F , Serdaroglu P , Vandenberghe A , Battaloglu E
Published: March 2003

The major Charcot–Marie–Tooth Type 1 (CMT1) locus, CMT1A, and Hereditary neuropathy with liability to pressure palsies (HNPP) cosegregate with a 1.5‐Mb duplication and a 1.5‐Mb deletion, respectively, in band 17p11.2. Point mutations in peripheral myelin gene 22 (PMP22), myelin protein zero (MPZ), and connexin 32 (Cx32) have been reported in CMT1, and in PMP22 in HNPP patients without deletion. We have screened 54 CMT1 patients, of variable clinical severity, and 25 HNPP patients from Turkey, with no duplication or deletion, for mutations in the PMP22 and Cx32 genes. A novel frameshift mutation affecting the second extracellular domain of PMP22 was found in an HNPP patient, while a point mutation in the second transmembrane domain of the protein was detected in a CMT1 patient. Two point mutations affecting different domains of Cx32 were identified in two CMTX patients. Another patient was found to carry a polymorphism in a non‐conserved codon of the Cx32 gene. The clinical phenotypes of the patients correlate well with the effect of the mutation on the protein.
The beta‐globin locus control region versus gene therapy vectors: a struggle for expression
Authors: Ellis J , Pannell D
Published: March 2003

Developmental control of gene expression has a major impact on the design of β‐globin retrovirus vectors for hematopoietic stem cell gene therapy of β‐thalassemia. It is obvious that the endogenous locus control region (LCR) elements that drive β‐globin gene expression in transgenic mice must be included in these vectors. However, the specific elements to use are not clear and require an understanding of LCR action. Moreover, retrovirus vectors contain silencer elements that function in stem cells and are dominant to LCR function. Recent studies on LCRβ‐globin transgenes and retrovirus silencing suggest ways to overcome this silencing effect after transfer into stem cells and carefully designed lentivirus vectors have exciting therapeutic benefit in animal models of β‐thalassemia. By building on 15 years of development, LCRβ‐globin vectors are now being tested in preclinical animal models and may ultimately lead to the long‐sought cure for this genetic disease.
An HphI polymorphism in the E‐selectin gene is associated with premature coronary artery disease
Authors: Zheng F , Chevalier JA , Zhang LQ , Virgil D , Ye SQ , Kwiterovich PO
Published: March 2003

An increased expression of E‐selectin has been observed in the arterial endothelium interacting with lymphocytes and macrophages in human atherosclerotic lesions. We examined whether a polymorphism in the E‐selectin gene, due to a G to T mutation (G98T) in the untranslated region of exon 2, was associated with premature coronary artery disease (CAD). Other lipid and nonlipid risk factors including a Ser to Arg (S128R) substitution in the E‐selectin gene were also assessed. In patients with premature CAD (men ≤45 years old and women ≤55 years old, N=51) who underwent an elective diagnostic coronary arteriography, the frequency of the mutation was significantly higher than in controls (N=50, 0.22 vs. 0.10, p=0.024). After controlling for other CAD risk factors (plasma total cholesterol, triglyceride, LDL‐apolipoprotein B, cigarette smoking and the S128R mutation) by multiple logistic analysis, the G98T mutation in the E‐selectin gene was still a significant predictor of premature CAD [p=0.022, odds ratio (95%, CI)=3.58 (1.20–10.67)].
Advances in the detection of chromosomal aberrations using spectral karyotyping
Authors: Bayani J , Squire JA
Published: March 2003

Spectral karyotyping (SKY) is a powerful 24‐color, whole chromosome‐painting assay allowing the visualization of each chromosome in one experiment. Subtle karyotype rearrangements can be detected easily so that small translocations lead to a transition from one color to another at the chromosomal breakpoint region. SKY has enabled the elucidation of several examples of hidden or ‘cryptic’ structural aberrations that may otherwise have been left undetected by classical cytogenetic methods. Furthermore, the chromosomal origins of abnormalities once designated ‘marker chromosomes’ can now be determined rather than left unidentified. SKY analysis of cancer cytogenetics samples provides a much more detailed description of the highly abnormal karyotypes that characterize advanced tumors and cancer cell lines. In addition, SKY significantly adds to the power of clinical cytogenetic analysis of constitutional chromosomal aberrations by facilitating the identification of subtle structural rearrangements that may contain aneuploidy with potential pathological consequences.
Severe valvular and aortic arch calcification in a patient with Gaucher's disease homozygous for the D409H mutation1
Authors: George R , McMahon J , Lytle B , Clark B , Lichtin A
Published: March 2003

Gaucher's disease is an autosomal recessive inherited defect of the lysosomal enzyme glucocerebrosidase, which leads to glucocerebroside accumulation in the reticuloendothelial system. Homozygosity for the D409H mutation has been associated with cardiovascular valvular disease. We present a case of a 17‐year‐old Palestinian patient who presented with severe aortic and mitral valvular calcification, as well as calcification of the ascending aorta, the aortic arch and the ostia of his coronary arteries. The patient was confirmed to be homozygous for the D409H mutation in the glucocerebrosidase gene. The patient's enzyme assay for glucocerebrosidase activity was 5 nm/h/mg protein (normal 13–22 nm/h/mg). The patient presented with symptoms of dyspnea and chest pain. He had a 6‐year history of documented aortic valve calcification by echocardiogram after two of his older brothers died of congestive heart failure and severe valvular calcification. Cardiac catheterization showed a severely calcified aorta with almost no motion of the aortic valve leaflets and severe calcification of the mitral valve and the mitral valvular apparatus. The patient underwent extensive cardiac surgery with aortic and mitral valve replacements and intraoperative findings confirmed calcification of the entire aortic root. Electron microscopy of the valves confirmed the presence of Gaucher's cells. Enzyme therapy with imiglucerase was initiated. The patient is in stable condition, 20 months post‐operatively.
Maternal component in the familial aggregation of hypertension
Authors: DeStefano AL , Gavras H , Heard‐Costa N , Bursztyn M , Manolis A , Farrer LA , Baldwin CT , Gavras I , Schwartz F
Published: March 2003

To assess maternal versus paternal contributions to the familial aggregation of hypertension, we examined family history data from 344 hypertensive probands (69 African American, 153 US Caucasian, 122 Greek Caucasian) ascertained without respect to parental hypertension status. The proportion of hypertensive mothers (81.7, 65.0 and 84.8% for African Americans, US Caucasians and Greek Caucasians, respectively) of these probands was significantly greater than the proportion of hypertensive fathers (50.0, 44.9 and 48.3%, respectively) in all three ethnic groups. The lifetime risk of hypertension was significantly greater for mothers compared with fathers of these hypertensive probands (p<0.001). Examination of the proband's siblings indicated that maternal history of hypertension was associated with greater lifetime risk for hypertension than paternal history (p<0.01). In conclusion, we observe a consistent maternal component in the inheritance of hypertension. Although we cannot separate a maternal genetic from epigenetic or environmental effect, our findings suggest that genetic research should include studies of the mitochondrial as well as nuclear genome. Furthermore, when assessing a patient's risk for hypertension, particular attention should be paid to the maternal family history.
Determination of a positive malignant hyperthermia (MH) disposition without the in vitro contracture test in families carrying the RYR1 Arg614Cys mutation
Authors: Rueffert H , Olthoff D , Deutrich C , Froster UG
Published: March 2003

Molecular genetic methods are used with caution for determining positive malignant hyperthermia (MH) disposition in clinical MH diagnosis because of the genetic variability of this disease. But under defined conditions, genotyping can have an advantage over the standardized in vitro contracture test (IVCT) in respect of invasive approach, specificity, patient compliance, and the work and expense involved in the method. We aim to demonstrate this using 10 families with the Arg614Cys mutation in the ryanodine receptor as an example.  Fifty‐one index patients who had been classified as MH‐susceptible (MHS) in the IVCT (European MH protocol) after a clinical MH incident or suspected MH were screened for the Arg614Cys (C1840→T) mutation in the RYR1 gene because this mutation is more common in German MH families (9%). The family members of those index patients, in whom a Arg614Cys mutation was detectable, were also screened for the presence of this mutation (n=136), and the results were subjected to a more detailed analysis including existing IVCT findings (n=71).  The Arg614Cys mutation was identified in a total of 64 members of the 10 independent families. In 35 individuals in this group, there was a definite concordance between the MHS diagnosis in the IVCT and the presence of the Arg614Cys mutation. No individual phenotyped as MH‐negative carried the mutation. On the basis of the guidelines of the EMHG for molecular genetic detection of MH susceptibility, 29 individuals who bore the Arg614Cys mutation were classified as MHS without the IVCT.  If a causal mutation is detected in an MH family, the MHS diagnosis can be deduced without the invasive IVCT in all other mutation carriers. Despite inclusion of only one (Arg614Cys) of all known MH mutations, the study emphasizes the practical use of a genetic approach for determination of a positive MH diagnosis.
Family‐based transmission disequilibrium test (TDT) and case–control association studies reveal surfactant protein A (SP‐A) susceptibility alleles for respiratory distress syndrome (RDS) and possible race differences
Authors: Floros J , Fan R , Matthews A , DiAngelo S , Luo J , Nielsen H , Dunn M , Gewolb I H , Koppe J , Van Sonderen L , Farri‐Kostopoulos L , Tzaki M , Rämet M , Merrill J
Published: March 2003

A key cause of respiratory distress syndrome (RDS) in the prematurely born infant is deficiency of pulmonary surfactant, a lipoprotein complex. Both low levels of surfactant protein A (SP‐A) and SP‐A alleles have been associated with RDS. Using the candidate gene approach, we performed family‐based linkage studies to discern linkage of SP‐A to RDS and identify SP‐A susceptibility or protective alleles. Moreover, we performed case–control studies of whites and blacks to detect association between RDS and SP‐A alleles. Transmission disequilibrium test (TDT) analysis revealed that the frequency of transmission (from parent to the offspring with RDS) of alleles 6A2 and 1A0 and of 1A0/6A2 haplotype in RDS was increased, whereas transmission of alleles 1A5 and 6A4 and of haplotype 1A5/6A4 was decreased. Extended TDT analysis further strengthened the observations made. The case–control studies showed that in whites or blacks with RDS the frequencies of specific genotypes, 1A0 and 6A2 or 1A0, were increased, respectively, but the frequency of specific 6A3 genotypes was increased in certain white subgroups and decreased in blacks. Regression analysis revealed gestational age (GA) and 6A3 genotypes are significant factors in blacks with RDS. In whites with RDS, GA and antenatal steroids are important factors. The data together indicate linkage between SP‐A and RDS; certain SP‐A alleles/haplotypes are susceptibility (1A0, 6A2, 1A0/6A2) or protective (1A5, 6A4, 1A5/6A4) factors for RDS. Some differences between blacks and whites with regard to SP‐A alleles may exist.
Hereditary breast/ovarian cancer – pitfalls in genetic counseling
Authors: Dagan E , Gershoni‐Baruch R
Published: March 2003

Genetic counseling and risk assessment, given to women with a family history of breast/ovarian cancer, are regularly based on pedigree analysis. In the Ashkenazi Jewish population, hereditary breast/ovarian cancer is mainly attributed to three founder mutations, namely, 185delAG, 5382insC, and 6174delT, in BRCA1/2 genes. The overall frequency of these mutations, in the Jewish Ashkenazi population, is as high as 2.5%. Based on clinical and family history data, the results of BRCA molecular testing, in Ashkenazi individuals at risk, are appropriately anticipated in most cases. Here we report on five families, in which the segregation of BRCA1/2 mutations, in affected and unaffected family members, was unexpected, emphasizing the need to test, for founder mutations, every Ashkenazi individual at risk, irrespective of the genotype of affected family members. Ultimately, risk assessments and recommendations, in Ashkenazi women, should be invariably based on the results of genetic testing.
Distribution of α1‐antitrypsin PI S and PI Z frequencies in countries outside Europe: a meta‐analysis
Authors: Blanco I , Bustillo EF , Rodriguez MC
Published: March 2003

The objective of the present study was to review published surveys on allelic frequencies S and Z in countries outside Europe to evaluate the validity of the reported data.  Studies on the topic, published from 1965 to May 2001, were retrieved using MEDLINE and bibliographic reference consultations.  The criteria for the selection of the studies were the following: 1) sample size ≥250 individuals; 2) α1‐antitrypsin phenotype determination performed by means of crossed antigen–antibody, isoelectric focusing in polyacrylamide gels, or polymerase chain reaction (PCR); 3) PI type determination performed without any previous screening procedure; 4) S and Z 95% CI of the reported outcomes within the limits of a calculated coefficient of variation.  Forty‐three out of 85 studies comply with the established criteria for being analysed. Worldwide maps of geographical distributions of PI S and PI Z frequencies have been designed by the authors by adding the data provided by these 43 selected studies to the 70 reported in a recent European meta‐analysis.
Familial Down syndrome: evidence supporting cytoplasmic inheritance
Authors: Arbuzova S , Cuckle H , Mueller R , Sehmi I
Published: March 2003

The frequently observed familial aggregation of Down syndrome (DS) 47,+21 and other aneuploidies and the phenomenon of double aneuploidy involving DS cannot be accounted for by chance alone. To clarify possible aetiological factors, pedigrees from all 7 affected families with repeated marriages referred to two regional genetics centres were examined. In each case the recurrence of aneuploidy was on the mother's side (p<0.01). Such a pattern suggests cytoplasmic inheritance of a risk factor. The hypothesis that mitochondrial DNA mutations have a role in the aetiology of DS is supported by other observations as well as by theoretical considerations.
Reproductive decisions of parents of children with metabolic disorders
Authors: Read CY
Published: March 2003

The Interaction Model of Client Health Behavior (IMCHB) served as a guide for variable selection and instrument development for telephone interviews with 230 parents of children with metabolic disorders. Sociodemographic, psycho‐affective and client–professional interaction variables were examined in relation to three outcomes: (1) receptivity to future prenatal diagnosis (56% were receptive); (2) likelihood of terminating an affected pregnancy (10% would); and (3) whether or not the parent had taken measures to prevent another affected pregnancy (41% had). All three outcomes were significantly correlated with higher scores on the Parent Stress Index, lower scores on the Vineland Adaptive Behavior Scales, fewer persons in the parent's social support network, greater worry about the living child's future and greater perceived difficulty meeting the child's extra care needs. A regression model constructed to explain taking measures to prevent a future affected pregnancy illustrated the usefulness of the IMCHB in research that involves multiple interacting variables on health outcomes. Few of the parents (7.4%) reported an interaction with a genetic counsellor, highlighting the need for practitioners from multiple disciplines to be adequately educated in principles of genetics, especially the psychological and affective aspects of counselling.
Evaluation of the needs of spouses of female carriers of mutations in BRCA1 and BRCA2
Authors: Metcalfe KA , Liede A , Trinkaus M , Hanna D , Narod SA
Published: March 2003

Metcalfe KA, Liede A, Trinkaus M, Hanna D, Narod SA. Evaluation of the needs of spouses of female carriers of mutations in BRCA1 and BRCA2. Clin Genet 2002: 62: 464–469. © Blackwell Munksgaard, 2002

The process of genetic testing involves the entire family, including spouses. The objective of this study was to measure the specific needs and to describe the experiences of spouses of women who received genetic counseling for a positive BRCA1/2 result. We surveyed 59 spouses of female mutation carriers. The mean length of relationships was 26 years (range: 2.5–50 years). All were supportive of their spouses' decision to undergo genetic testing and counselling. Four respondents stated that they wished that they had received additional support at the time of test disclosure and 20% felt that their wives had received inadequate support. One‐quarter of the spouses believed that their relationship had changed because of genetic testing; most felt that they had become closer to their wives. Husbands were most concerned about the risk of their wife dying of cancer (43%), followed by the risk of their spouse developing cancer (19%) and the risk that their children would test positive for the BRCA mutation (14%). Distress levels, measured by the Impact of Event scale, suggest that few spouses were experiencing clinical levels of distress.
Polymorphisms at the SRBI locus are associated with lipoprotein levels in subjects with heterozygous familial hypercholesterolemia
Authors: Tai ES , Adiconis X , Ordovas JM , Carmena‐Ramon R , Real J , Corella D , Ascaso J , Carmena R
Published: March 2003

Scavenger receptor, class B, type 1 (SRBI) is a promising candidate gene involved in the pathophysiology of atherosclerosis. We have examined the association of three common polymorphisms at the SRBI locus in 77 subjects who were heterozygous for familial hypercholesterolemia (FH). The alleles represented by polymorphisms in exon 1 and exon 8 were associated with variation in plasma concentrations of fasting triglyceride (TG). Mean plasma TG concentrations for homozygotes for the most common allele, and for heterozygotes and homozygotes for the less common allele were 85 ± 6, 111 ± 9 and 135 ± 22 mg/dl (p = 0.011) for exon 1, and 96 ± 11, 86 ± 6 and 134 ± 13 mg/dl (p = 0.007) for exon 8, after adjustment for age, sex and body mass index. In addition, the exon 8 polymorphism was associated with increased total cholesterol (320 ± 15, 340 ± 8 and 388 ± 18 mg/dl, p = 0.015), very low density lipoprotein (VLDL) cholesterol (18 ± 2.9, 15.7 ± 1.6 and 33.4 ± 3.9 mg/dl, p < 0.001) and low density lipoprotein (LDL) cholesterol (251 ± 15, 270 ± 8 and 312 ± 10 mg/dl, p = 0.041) concentrations. In agreement with animal studies, our data also suggest a role for the SRBI in the metabolism of apolipoprotein B (apoB)‐containing lipoproteins in humans. This pathway may constitute a backup mechanism to LDL receptor‐mediated pathways for the catabolism of these lipoproteins, which could be particularly relevant in subjects with high levels of apoB‐containing lipoproteins, such as those occurring in patients with FH.
Severe arteriolar lesion mimicking drug‐induced arteriolopathy in a long‐term surviving renal allograft
Authors: Nazneen Arifa , Nishikido Masaharu , Koga Shigehiko , Kanetake Hiroshi , Liu Diange , Harada Takashi , Taguchi Takashi
Published: March 2003

Abstract: We report severe arteriolar lesion mimicking drug‐induced arteriolopathy in a renal allograft of a 37‐year‐old Japanese male, who has been treated by conventional immunosuppressive therapy but not administered cyclosporin or tacrolimus for 16 years after renal transplantation. Renal biopsy also showed glomerular changes including transplant glomerulopathy and features of chronic vascular rejection. The cause of the arteriolar lesion remains uncertain. Although its pathogenesis may be multi‐factorial, long‐term usage of conventional immunosuppressive agents and/or vascular rejection may contribute to the occurrence of the arteriolar lesion. We propose that biopsy study is needed for further understanding of histopathological behaviours of renal grafts in long‐term survivors.
A case of chronic renal allograft failure by effects of elderly donor
Authors: Kim Yong‐Jin , Kim Yong‐Lim
Published: March 2003

Abstract: We experienced a case of chronic renal allograft failure from an elderly donor. A 23‐year‐old man received living‐related transplantation in 1998. The donor was his father, 66 years old and 69 kg body weight. The recipient was 88 kg and the cause of the renal failure was IgA nephropathy. The graft function decreased 2 months after transplantation. One year later, proteinuria and haematuria developed. Six months later, when the creatinine rose to 2.5 mg/dL, a renal transplant biopsy was performed. Characteristic microscopic features were: diffuse segmental to global glomerulosclerosis, hypertrophy of non‐sclerotic glomerulus, tubular atrophy, arteriolar hyalinosis, interstitial lymphocytic infiltration with tubulitis and anti‐IgA deposition on glomeruli. The pathological diagnoses were recurrent IgA nephropathy, acute rejection and chronic cyclosporin nephrotoxicity. Diffuse glomerulosclerosis as well as glomerular hypertrophy might be the end result of hyperfiltration, which was a consequence of a small number of functioning nephrons. The old age of the donor and the heavy body weight of the recipient could be risk factors for this case.
Differential diagnosis of kidney transplant rejection and cyclosporin/tacrolimus nephropathy using urine cytology
Authors: Kyo Masahiro , Ichikawa Yasuji , Toki Kiyohide , Nishimura Kennichi , Fukunishi Takanobu , Nagano Shunsuke , Namba Yukiomi , Gudat Fred , Dalquen Peter , Mihatsch M J
Published: March 2003

Abstract: A total of 9000 urine samples from 69 kidney transplant recipients were studied for differential diagnoses of transplant rejection and cyclosporin/tacrolimus toxicity. New–Sternheimer and Papanicolaou staining were used to differentiate cells in urine. We also employed an immunocytochemical technique for further identification of exfoliated cells. With New–Sternheimer and Papanicolaou staining, the predominance of proximal tubular cells was useful to differentiate cyclosporin/tacrolimus toxicity from acute rejection in cases of increased serum creatinine level. During rejection episodes, an increased number of mononuclear cells and renal epithelial cells were found. Immunocytochemical analysis showed a significant increase of CD2‐, CD4‐ CD8‐, CD25‐ and HLA‐DR‐positive cells with rejection. However, there was no relationship between Banff criteria rejection grade and the increase of mononuclear cells.
Renal transplantation for end‐stage renal disease following bone marrow transplantation: A report of six cases, with and without immunosuppression
Authors: Butcher Julie A , Hariharan Sundaram , Adams Mark B , Johnson Christopher P , Roza Allan M , Cohen Eric P
Published: March 2003

Background. Over 12 000 bone marrow transplantations (BMT) are performed in the USA each year. This procedure is associated with significant morbidity including acute and chronic renal failure (CRF). CRF after BMT is usually secondary to radiation nephropathy and/or cyclosporine (CsA) toxicity. Survival on dialysis therapy for patients with radiation nephropathy is poor and renal transplantation may be a preferable form of renal‐replacement therapy.Methods. We report our experience with renal transplantation in 6 patients with end‐stage renal disease (ESRD) following BMT: 4 as a result of radiation nephropathy; one secondary to hemolytic–uremic syndrome; and 1 as a result of antitubular basement membrane nephritis. Ages at the time of BMT ranged from 26 to 40 yr. ESRD developed after a mean period of 94 months (range 42–140 months) after BMT. The kidney source was from a living donor in 5 patients, and a cadaveric donor (CAD) in 1 patient. In 3 recipients, the bone marrow and kidney were from the same donor. They are managed without any immunosuppressive therapy. The other 3 were initiated on triple therapy (prednisone, mycophenolate mofetil/azathioprine and cyclosporine/tacrolimus).Results. These patients have been followed for up to 31 months (range 3–30 months) after kidney transplant, and 5 out of 6 are alive with functioning bone marrow and renal transplants. Their plasma creatinines range from 70 to 160 μmol/L (mean 97 μmol/L). One patient died following metastatic squamous cell cancer of the genital tract.Conclusions. 1) Renal transplant is a feasible alternative for patients with ESRD following BMT; 2) if bone marrow and kidney are from the same donor, the recipient requires little or no maintenance immunosuppression; 3) short‐term results show good survival, but long‐term follow‐up is needed; 4) infections and malignancy post‐renal transplantation were seen in recipients who needed immunosuppression; and 5) reduction in immunosuppression may be needed in such post‐BMT patients who undergo kidney transplants.
Functional, life‐threatening disorders and splenectomy following liver transplantation
Authors: Troisi R , Hesse Uj , Decruyenaere J , Morelli Mc , Palazzo U , Pattyn P , Colardyn F , Maene L , De Hemptinne B
Published: March 2003

Splenectomy (SPL) in cirrhotic patients undergoing liver transplantation (LTx) may resolve specific problems related to the procedure itself, in case of functional and life‐threatening clinical situations often occurring as a result of liver cirrhosis and portal hypertension.

Methods. A single‐center experience of ten splenectomies in a series of 180 consecutive adult liver transplant patients over a period of 6 yr is reported. The mean patient age was 46.8±9.5 yr (range 25–57 yr). Indications for SPL were post‐operative massive ascitic fluid loss (n=3), severe thrombocytopenia (n=3), acute intra‐abdominal hemorrhage (n=2), infarction of the spleen (n=1), and multiple splenic artery aneurysms (n=1).

Results. Extreme ascites production due to functional graft congestion disappeared post‐SPL, with an improvement of the hepatic and renal functions. SPL was also effective in cases of thrombocytopenia persistence post‐LTx, leading to an increase in the platelet count after about 1 wk. Bleeding episodes related to left‐sided portal hypertension or trauma were also resolved. The rejection rate during hospitalization was 0%, and no other episodes were recorded in the course of the long‐term follow‐up. However, sepsis with a fatal outcome occurred in 4 patients, i.e. between 2 and 3 wk post‐SPL in three cases and 1 yr after the procedure as a result of pneumococcal infection in the last case. Fatal traumatic cranial injury occurred 3 yr post‐LTx in another case. Five patients (50%) are still alive and asymptomatic after a median follow‐up period of 36 months.

Conclusions. The lowering of the portal flow appears to resolve unexplained post‐operative ascitic fluid loss as a result of functional graft congestion following LTx. However, because of the enhanced risk of SPL‐related sepsis, a partial splenic embolization (PSE) or a spleno‐renal shunt could be used as an alternative procedure because it allows us to preserve the immunological function of the spleen. SPL is indicated in case of post‐transplant bleeding due to left‐sided portal hypertension and trauma, spleen infarction, and to enable prevention of hemorrhage in liver transplant patients with multiple splenic artery aneurysms. Severe and persistent thrombocytopenia could be treated with PSE. Because the occurrence of fatal sepsis post‐SPL is a major complication in LTx, functional disorders, such as ascites and thrombocytopenia, should be treated with a more conservative approach.