bluuebunny/crossref_metadata_2025 huggingface dataset:
Relation between Carotid Intima-Media Thickness, Platelet Surface Activation and Endothelial Cell Markers
Authors: Ramsis Nevene , El-Hawary Ahmed A. , Ismail Emad
Published: April 2003

Background: The role of platelet activation and endothelial cell damage in the pathogenesis of atherosclerosis was investigated. Methods: Flow-cytometric detection of platelet activity was accomplished by measuring the surface expression of activated platelet glycoprotein IIb/IIIa (activated CD41) and the lysosomal integral membrane protein (CD63). Levels of thrombomodulin (TM) and von Willebrand factor (vWF) were estimated by the ELISA technique as markers of endothelial cell damage. These procedures were performed in healthy male subjects without obvious signs of atherosclerosis. Also, the intima-media thickness of the carotid artery was measured with high-resolution B- mode ultrasound to quantitate the presence and/or the extent of carotid atherosclerosis. Results: According to ultrasound findings patients were divided into those with apparent evidence of atherosclerosis (AS+) with intima-media thickness >1.1 mm (n = 19) and those without such evidence (AS–) with intima-media thickness <1.1 mm (n = 17). The percentages of activated CD41 and CD63 surface antigen expression were significantly increased in the AS+ compared to AS– subjects. TM levels were elevated in the former group compared to the latter, while vWF levels were not different in the two groups. Multivariate analysis indicated the independent association of carotid atherosclerosis with each of the expression of activated CD41, CD63 as well as TM levels after adjustment of other risk factors. Conclusion: This study demonstrates that platelets circulate in an enhanced activation state in asymptomatic atherosclerosis, which is closely related to the degree of endothelial cell damage as expressed by increased plasma levels of TM. The detection of platelet activation can be used as a potential marker for oncoming atherosclerosis.
The Beneficial Effect of a β-D-Xyloside, Iliparcil, in the Prevention of Postthrombolytic Rethrombosis in the Rat
Authors: Chicaud P. , Rademakers J.R. , Millet J.
Published: April 2003

The effect of Iliparcil, a new orally active β-D-xyloside venous antithrombotic, was studied on the rethrombosis following thrombolytic therapy in rats, using a modified Umetsu model. The drug was administered by oral route prior to thrombolytic therapy, which consisted of administering a combination of heparin and urokinase (H/U) at 37.5 and 70,000 IU/kg, respectively. Time to reocclusion increased from 3.9 min with saline to 10.5 min following H/U injection. When Iliparcil (30 mg/kg, oral route) was administered 4 h before H/U injection, the time to reocclusion was increased by 250% compared with H/U alone (p < 0.001). Similarly, dermatan sulfate (DS), administered intravenously (3 mg/kg) 5 min before thrombus induction, also increased the time to reocclusion (300% compared with H/U alone; p < 0.001). It was also shown that times to reocclusion following Iliparcil or DS treatments were still increased even when heparin dosage was decreased. These results suggest that an antithrombotic product derived from the β-D-xyloside family could be advantageously used in combination with thrombolytic treatment instead of heparin, which causes complications and side effects.
Conjectures and Refutations on the Mode of Action of Heparins
Authors: Béguin S. , Welzel D. , Al Dieri R. , Hemker H.C.
Published: April 2003

Low-molecular-weight heparins (LMWHs), like unfractionated heparin (UFH), exert their action primarily by accelerating the interaction between antithrombin (AT) and thrombin. At the levels of aXa activity that are attained in human pharmacology, it does not cause significant (>15%) inhibition of the clotting system. The essential differences between LMWHs and UFH are: (a) LMWHs attain higher plasma concentrations after subcutaneous injection (high bioavailability), and (b) in contrast to LMWHs, UFH contains very large heparin molecules with a putative hemorrhagic action. The reputedly higher aXa activity of LMWH can be shown to be largely due to the absence of Ca2+ using the current laboratory methods to estimate this activity. Via this artifact the apparently high aXa activity of LMWHs is correlated but not related to their favorable pharmacokinetic properties. Consequently dosage guidelines for the use of different LMWHs cannot be based upon their aXa activity. Until better laboratory methods are available, clinical results are the only reliable guideline to heparin dosage.
Acquired Bernard-Soulier Syndrome: A Case with Necrotizing Vasculitis and Thrombosis
Authors: Tornai Istvan , Boda Zoltan , Schlammadinger Agota , Juhasz Attila , Cauwenberghs Nancy , Deckmyn Hans , Harsfalvi Jolan
Published: April 2003

We describe a patient with positive antinuclear antibodies, polyclonal gammopathy and high level of circulating immunocomplexes, resulting in vascular purpura. In addition, the patient had a slightly prolonged bleeding time and an isolated defect of ristocetin-induced platelet aggregation (RIPA) in platelet-rich plasma (PRP). The patient’s plasma also inhibited RIPA in normal PRP and in normal platelet suspension. The activity and multimeric structure of plasmatic von Willebrand factor showed no alteration. We could demonstrate an autoantibody against platelet membrane glycoprotein (GP) Ib, using an ELISA-type assay. These data suggest an acquired Bernard-Soulier syndrome. We suggest that the patient had an immunocomplex-mediated leukocytoclastic vasculitis accompanied by production of antinuclear autoantibodies as well as the presence of an autoantibody against GPIb. The titer of the anti-GPIb antibody, however, was too low to induce significant platelet-type bleeding tendency, only laboratory alterations were found. Moreover, in a later stage of her disease, she developed a severe necrotizing vasculitis which was followed by a deep venous thrombosis.
The FVII Activating Protease Cleaves Single-Chain Plasminogen Activators
Authors: Römisch Jürgen , Vermöhlen Sylvia , Feussner Annette , Stöhr Hans-Arnold
Published: April 2003

A serine protease isolated from plasma sharing structural characteristics with a hepatocyte growth factor activator-like protease has been demonstrated recently to activate FVII. Accordingly, it was named ‘FVII activator’. Until now an impact of this protease on the fibrinolytic system has not been reported. We islolated the protease from cryo-poor plasma by subsequent ion exchange chromatography and adsorption to immobilized heparin and/or aprotinin. Incubation of single-chain plasminogen activators (sc-PAs) with the FVII activator revealed significant activation of urokinase sc-PA (scu-PA) and tissue sc-PA (sct-PA) in vitro. It was enhanced in the presence of calcium and heparin. Compared to kallikrein, a more efficient activation of scu-PA was observed, whereas sct-PA appeared to be a poorer substrate for the FVI activator. At low protease concentrations and in the presence of heparin the scu-PA activation was comparable to plasmin. Employing recalcified whole blood thrombelastography, the lysis of initially formed fibrin was observed after addition of a combination of scu-PA and the FVII activator, whereas the scu-PA alone had a negligible effect at the concentration used. The study results as presented demonstrate that the FVII activator is a potent activator of sc-PAs in vitro. Whether it plays a physiological role in fibrinolysis deserves further investigation. Its comparatively high affinity to heparin assumes a function in cell surface or matrix events.
From Ought to Is: A Neo-Marxist Perspective on the Use and Misuse of the Culture Construct
Authors: Baumrind Diana
Published: April 2003

Neo-Marxist Standpoint Theory is concerned with the application of moral judgment to praxis. A standpoint is a perspective from which particular features of reality are brought into sharp perspective and other features obscured. When application rather than judgment is construed as central to morality the formal criteria of prescriptivity and primacy, but not of universalizability and impartiality, are constitutive. The moral province thus construed is not limited to issues of welfare and justice towards others, although these are primary, but includes existential obligations to the self, and internalized preemptive obligations to observe religious and social customs. Moral beliefs are grounded in cultural contexts. Culture, however, is not a static entity, but rather a dynamic process subject to change in response to internal contradictions and critical social thought. Furthermore, there are multiple standpoints within a culture, as well as distinctive values shared by members of a culture. Although the dominant morality in any society serves to justify the interests of its ruling class, it is the standpoint that represents the interests of the oppressed that is more valid because it is fairer, more comprehensive and more progressive. If the reduction of oppression is accepted as a superordinate social good then this judgment applies also to societies which justify oppressive practices by claiming that they are intrinsic to the identity of the culture of that society.
A Social Pragmatic Model of Talk: Implications for Research on the Development of Children’s Social Understanding
Authors: Turnbull William , Carpendale Jeremy I.M.
Published: April 2003

We present a social pragmatic model of talk-as-interaction. Talk consists of observable and orderly sequences of turns by means of which participants together construct and interpret action. The meaning of a speaker’s turn, the action accomplished, is observable in the manifest details of that turn and responses to it. We discuss methodological implications and illustrate the relevance of this social pragmatic model for theory and research on human development through an analysis of the role of talk in the development of children’s understanding of mental states.
Beyond Individualism and Sociocentrism: An Ontological Analysis of the Opposing Elements in Personal Experiences of Japanese Adolescents
Authors: Shimizu Hidetada
Published: April 2003

Many studies of Japan have used the ‘sociocentric’ (i.e., contextual, collective and empathic, etc.) framework of analysis to contrast Japanese culture, people, or behavior with their arguably individualistic counterparts in America (or ‘Western societies’). This article argues that the individualism-sociocentrism dichotomy as applied uniformly (e.g., all or the majority of Japanese are sociocentric) and exclusively (e.g., Japanese are sociocentric but not individualistic, unlike Americans who are individualistic, but not sociocentric) to a group of people such as those in Japan is methodologically limited and conceptually inadequate to understand private experiences of its individual members. Placing case studies of three adolescents in the ontological perspective of Heidegger and Paul Tillich, I will show that the two orientations are mutually dependent and dynamically constituting elements of their personal experiences.
Extreme Selection Strategies in Gene Mapping Studies of Oligogenic Quantitative Traits Do Not Always Increase Power
Authors: Allison David B. , Heo Moonseong , Schork Nicholas J. , Wong Su-Ling , Elston Robert C.
Published: April 2003

It is well known that obtaining adequate statistical power to detect linkage to or association with genes for complex quantitative traits can be very difficult. In response, investigators have developed a number of power-enhancing strategies that consider restraints such as genotyping (and/or phenotyping) costs. In the context of both association and sib pair linkage studies of quantitative traits, one of the most widely discussed techniques is the selective sampling of phenotypically extreme individuals. Several papers have demonstrated that such extreme sampling can markedly increase power (under certain circumstances). However, the parenthetical phrase in the previous sentence has generally not been made explicit and it appears to be implied that the more phenotypically extreme the individuals, the more power one has. In this paper, we show by simulation that this is not true under all circumstances. In particular, we show that under oligogenic models, where some biallelic quantitative trait loci (QTLs) have markedly asymmetric allele frequencies and large mean displacement among genotypes, and others have less asymmetric allele frequencies and smaller mean displacement among genotypes, power to detect linkage to or association with the latter QTL can actually decrease by sampling more extreme sib pairs. This suggests that more extreme sampling is not always better. The ‘optimal’ sampling scheme may depend on both what one suspects the underlying genetic architecture to be and which of the oligogenic QTL one has greatest interest in detecting.
Familial Psoriasis and HLA-B: Unambiguous Support for Linkage in 97 Published Families
Authors: Leder Richard O. , Mansbridge Jonathan N. , Hallmayer Joachim , Hodge Susan E.
Published: April 2003

The existence of a psoriasis susceptibility locus, PSORS1 (HUGO/GDB-approved symbol), in or near the HLA region of chromosome 6 is strongly supported by a lod score analysis of HLA-B and psoriasis in 97 families from 16 published datasets. Families included in the dataset represent all the psoriasis families with usable HLA data that we could find in the published literature through May 1997. The recombination fraction between PSORS1 and HLA-B is estimated to be at or near 0.00, with a maximum two-point lod score of 23.7, assuming a dominant mode of inheritance with low (20%) penetrance at the PSORS1 locus. Although these families are geographically and ethnically diverse, there is no evidence for linkage heterogeneity at the HLA-linked locus in this analysis. We also conclude that the HLA-B17 allele, which is strongly associated with psoriasis, is unlikely itself to contribute directly to psoriasis susceptibility; rather, the HLA-B locus is probably tightly linked to the PSORS1 locus. Finally, we raise the possibility of a two-locus/heterogeneity model as one way to reconcile several findings in the literature.
High Variability of CYP21 Gene Rearrangements in Spanish Patients with Classic Form of Congenital Adrenal Hyperplasia
Authors: Lobato M. Natividad , Aledo Rosa , Meseguer Anna
Published: April 2003

Mutations that cause deficiency of the 21-hydroxylase (21-OH) appear as a result of recombinations between the CYP21B coding gene and the highly homologous CYP21A pseudogene, which are tandemly arranged with the C4A and C4B genes. We report a detailed analysis of a major chromosomic rearrangement by Southern blot using 21-OH and complement C4 cDNA probes, in a wide sample of classic Spanish congenital adrenal hyperplasia (CAH) patients. This study made it possible to observe that 50% of the patients carried at least one allele with gross abnormalities and that the frequencies of alleles with large deletions (16.66%) and gene conversions (14.16%) in the CYP21B gene were very similar. Moreover, our analysis revealed the existence of sixteen different restriction patterns of C4/CYP21 genes. Besides the detection of a new haplotype, which does not seem to appear from unequal crossing-over mechanisms, we observed the highest frequency on CYP21A duplications reported, as well as no duplications of the CYP21B gene. We also observed that although gross abnormalities of the CYP21A pseudogene did not affect 21-OH activity, alleles carrying deleterious point mutations had more rearrangements of the CYP21A gene than normal alleles. Even though the 21-OH deficiency is an autosomic trait, boys in our sample carried 2.6 times more deletions than girls. In contrast, conversion alleles were found equally frequently.
CA Repeat Polymorphism of theCOL6A3 Gene on Chromosome 2 q37
Authors: Pan Te-Cheng , Zhang Rui-Zhu , Speer Marcy C. , Chu Mon-Li
Published: April 2003

A CA dinucleotide repeat has been identified in an intron of the human α3(VI) collagen gene (COL6A3) located on chromosome 2q37. Analysis of 100 chromosomes in unrelated Caucasians has demonstrated the existence of eight alleles, and the allelic frequencies have been determined.
Repetitive Exon 45/46-Related Sequences of Human Ca2+ Channel α1C Subunit Gene
Authors: Soldatov N.M. , Raudsepp T. , Chowdhary B.P.
Published: April 2003

We found in the Ca2+ channel α1C subunit gene a new repetitive element of three paired exon 45/46-related sequences. We also identified a new exon 45/46-related sequence in the human genome and mapped it by fluorescence in situ hybridization to the 12p11.2 and 12p13.2-p13.1 bands. These positions are not recognized by DNA probes generated from the 5′- and 3′-terminal regions of the α1C gene. A possible existence of a new genomic homologue of the α1C subunit gene is discussed.
Low-Order Polynomial Trends of Female-to-Male Map Distance Ratios along Human Chromosomes
Authors: Li Wentian , Fann Cathy S.J. , Ott Jürg
Published: April 2003

Recombination rates in humans tend to be sex specific. For a given map interval delimited by genetic markers, the difference between male and female recombination rates may be measured by the ratio, R, of female-to-male map distance. On average over all chromosomes, R is close to 2, but this ratio is region specific. The spatial variation of R can be captured by a low-order (linear, quadratic, etc.) trend across the length of the chromosome. Chromosome maps have been constructed that take into account such trends. Resulting map distances tend to be more accurate than when such trends are ignored. These maps may be obtained at URL ftp://linkage.rockefeller.edu/SexSpecMaps/.
Multi-Locus Nonparametric Linkage Analysis of Complex Trait Loci with Neural Networks
Authors: Lucek Paul , Hanke Jens , Reich Jens , Solla Sara A. , Ott Jürg
Published: April 2003

Complex traits are generally taken to be under the influence of multiple genes, which may interact with each other to confer susceptibility to disease. Statistical methods in current use for localizing such genes essentially work under single-gene models, either implicitly or explicitly. In genomic screens for complex disease genes, some of the marker loci must be in tight linkage with disease susceptibility genes. We developed a general multi-locus approach to identify sets of such marker loci. Our approach focuses on affected sib pair data and employs a nonparametric pattern recognition technique using artificial neural networks. This technique analyzes all markers simultaneously in order to detect patterns of locus interactions. When applied to previously published sib pair data on type I diabetes, our approach finds the same genes as in the published report in addition to some new loci. For a specific two-locus model of inheritance, the power of our approach is higher than that of the currently used analysis standard.
Simple Tandem Repeat Polymorphisms in the Neuronal Nitric Oxide Synthase Gene in Different Ethnic Populations
Authors: Grasemann Hartmut , Drazen Jeffrey M. , Deykin Aaron , Israel Elliot , De Sanctis George T. , Pillari Anthony , Yandava Chandri N.
Published: April 2003

Allelic frequencies of a CA dinucleotide repeat in exon 29 and an intronic AAT trinucleotide repeat in the neuronal nitric oxide synthase (NOS1) gene were determined by simple sequence length polymorphism (SSLP) in 305 American-Caucasian and 105 African-American healthy subjects. There were highly significant differences in allele frequencies between the two ethnically diverse study populations.
A Survey of 1,000 Cases Referred for Cytogenetic Study to King Khalid University Hospital, Saudi Arabia
Authors: Al Husain Muneera , Zaki Osama K.
Published: April 2003

We reviewed cytogenetic studies that have been done in 1,000 consecutive non-oncology samples that were referred to the Cytogenetics Unit at King Khalid University Hospital, Riyadh, Saudi Arabia. The cases were grouped according to the referral diagnosis and the requested cytogenetic service. The frequency of the different types of numerical and structural abnormalities was determined and the relative frequency of cases with abnormal karyotype was calculated in each group. This study should assist physicians in Saudi Arabia and surrounding countries by increasing the awareness of the frequency of cytogenetic abnormality in different diagnostic groups. It also gives figures for comparison with other countries and research centers.
Heterogeneity for Multiple Disease Loci in Linkage Analysis
Authors: Bhat Ajita , Heath Simon C. , Ott Jürg
Published: April 2003

Many mendelian traits show heterogeneity; that is, the disease phenotype in different families may be caused by genes at different locations. In linkage analysis, this admixture type of heterogeneity (locus heterogeneity) has often been accommodated with one of the HOMOG programs, which thus far have been restricted to at most two disease gene locations. Here, an extension to an arbitrary number of disease locations is described. It has been implemented in a computer program, HOMOGM. This approach is also suitable as an approximation to the situation of complex traits, in which multiple disease genes may occur in the same family.
Cystic Fibrosis Mutations: Report from the French Registry
Authors: Guilloud-Bataille Monique , De Crozes Dauphine , Rault Gilles , Degioanni Anna , Feingold Josué
Published: April 2003

Data from 2,666 patients with cystic fibrosis (CF) born in France, submitted during the period of 1992–1996 to the French registry for CF, were used to describe the different mutations, their frequency and their regional distribution. A total of 5,332 CF chromosomes have been analyzed, demonstrating 229 different mutations and accounting for 87% of CF genes in the French population. ΔF508 is the most common mutation at 67.9% of CF mutations, followed by G542X (2.5%), N1303K (2.0%), 1717–1G→A (1.2%), R553X (0.8%) and G551D (0.7%). The data show a clear geographical variation in the distribution of many of the mutations. Given the geographical heterogeneity of these mutations, carrier screening does not appear to be feasible in most French regions.
Molecular Heterogeneity of the Glucose-6-Phosphate Dehydrogenase Deficiency in the Hellenic Population
Authors: Menounos Panayotis , Zervas Christos , Garinis George , Doukas Costantinos , Kolokithopoulos Dimosthenis , Tegos Costantinos , Patrinos George P.
Published: April 2003

We report results from a systematic study to identify the molecular basis of glucose-6-phosphate dehydrogenase (G6PD) deficiency on a sample of 299 male subjects from the Hellenic population. Our stepwise approach involved partial biochemical characterization and quantitation of the enzyme’s activity, MboII restriction endonuclease digestion to identify the G6PD Mediterranean variant, which represents the most frequent G6PD variant in our population and a nonradioactive polymerase chain reaction-single-strand conformation polymorphism methodology for the detection of the underlying molecular defect(s) in the rest of the non-Mediterranean G6PD-deficient individuals. Through this approach, six different G6PD variants were identified (G6PD Mediterranean, G6PD Hermoupolis, G6PD Cassano, G6PD Seattle, G6PD Ierapetra and G6PD Acrokorinthos), two of which were new (G6PD Hermoupolis, G6PD Acrokorinthos). In essence, this study underlines the remarkable genetic heterogeneity of the G6PD deficiency in the Hellenic population, while the finding of the double mutant, G6PD Hermoupolis, may help to outline the relationship and evolution of mutations in the human G6PD locus.
High Frequency of HLA-DQB1 Non-Asp57 Alleles in Kuwaiti Children with Insulin-Dependent Diabetes mellitus
Authors: Haider M.Z. , Shaltout A. , Alsaeid K. , Al-Khawari M. , Dorman J.S.
Published: April 2003

The prevalence of polymorphic amino acids at position 57 of the HLA DQB1 in Kuwaiti children with insulin-dependent diabetes mellitus (IDDM) and nondiabetic controls has been determined using a polymerase chain reaction-sequence-specific primers (PCR-SSP) method. Using this approach, 34/55 (62%) IDDM children were found to be homozygous Ala/Ala and 19/55 (35%) were heterozygous with various combinations. Amongst the IDDM children with heterozygous genotype at codon 57 of HLA DQB1, 6/55 (11%) had Asp/Ala, 8/55 (15%) had Ala/Val, 4/55 (7%) had Ala/Ser and 1/55 had Asp/Val allelic combinations. When considered collectively, the nonaspartate (NA) alleles were represented in 87% of the IDDM cases and only 13% cases had Asp57 allele in different heterozygous combinations, while none of the IDDM subjects had a homozygous Asp genotype. In nondiabetic controls, homozygous non-Asp (NA) alleles were represented in 44% subjects, 37% of the controls were heterozygous (NA/A) and 19% had a homozygous (A/A) genotype. These differences between the IDDM group and the control group were found to be statistically significant. Our data report one of the highest frequency of NA/NA residues at this locus compared with that from different world populations (Sardinians, Norwegians, US Caucasians, US Blacks and Chinese).
Gene-Environment Interactions and the Affected-Sib-Pair Designs
Authors: Guo Sun-Wei
Published: April 2003

In genetic mapping of complex traits, the affected-sib-pair method (ASP) and the transmission disequilibrium test (TDT) are two methods of choice. The major appeal of both ASP and TDT is that they do not require the knowledge of mode of inheritance underlying the trait in question. The relative ease and economy for data collection also is the reason for their popularity. The basic idea of the ASP is to identify genes or chromosomal regions through identifying genetic similarity based on phenotypical similarity. TDT, on the other hand, detects susceptibility genes through detecting unusual transmission patterns in families. Since phenotypic similarity can also be caused by environmental similarity, we investigate how the presence of gene-environment interaction (GEI) affects the power of both methods. For a simple one-locus-one-risk-factor model, our results indicate that, in the presence of GEI, methods developed based on marginal penetrance functions (i.e. ignoring the risk factor) can give spurious results. The triangular restriction on allele-sharing probability may no longer be valid. If the environment effect is strong, using exposure-discordant affected sib pairs may have advantage over other designs. Above all, a genetic model involving both genetic and environmental factors behaves differently from a single-locus genetic model.
Prevalence of CCR5 and CCR2 HIV-Coreceptor Gene Polymorphisms in Belgium
Authors: Struyf Frank , Thoelen Inge , Charlier Nathalie , Keyaerts Els , van der Donck Ingrid , Wuu Joanne , van Ranst Marc
Published: April 2003

Polymorphisms of the chemokine receptor genes CCR5 and CCR2 are associated with resistance to HIV-1 infection or delayed progression to AIDS. Few data are available on their combined prevalence in healthy subjects; we therefore examined the occurrence of CCR5-Δ32 and CCR2-64I polymorphisms in a sample of 310 healthy Belgians. Allele frequencies were 0.119 and 0.074 for CCR5-Δ32 and CCR2–64I, respectively. Genotype distributions for both polymorphisms were found to be in accordance with Hardy-Weinberg equilibrium, but a significant (p = 0.002) linkage disequilibrium between CCR5-Δ32 and CCR2-64I was observed. The high prevalence of CCR5-Δ32 and CCR2-64I in Belgians may need to be taken into account in the design of studies of antiretroviral treatments.
Monilethrix: Mutational Hotspot in the Helix Termination Motif of the Human Hair Basic Keratin 6
Authors: Horev L. , Glaser B. , Metzker A. , Ben-Amitai D. , Vardy D. , Zlotogorski A.
Published: April 2003

Monilethrix is a rare autosomal dominant disease characterized by hair fragility and follicular hyperkeratosis. Mutations in the human basic hair keratins hHb1 and hHb6 have recently been reported in this disease. Twelve families and sporadic cases were clinically diagnosed with monilethrix and were available for the study. The gene segment encoding the helix termination motif region of keratin hHb6 was PCR amplified and sequenced. Mutations were recognized in 6 families. Four families had the previously described mutations, Glu413Lys and Glu413Asp. In 2 unrelated families, a novel mutation, Glu402Lys, was identified. No clear association was found between the severity of the phenotype and the mutation carried. Furthermore, heterozygous members of the same family had variable degrees of hair and skin involvement. Homozygous patients identified in one large consanguineous family were more severely affected. Other genetic or environmental factors may also play a role in monilethrix.
Risk Ratios for Obesity in Families of Obese African-American and Caucasian Women
Authors: Price R. Arlen , Lee Joseph H.
Published: April 2003

We examined age- and sex-standardized risk ratios (SRRs) in matched samples of 1,185 families of obese African-American and Caucasian women. Familial risk ratios increased with body mass index (BMI) of proband and BMI thresholds of relative. Ratios were higher in Caucasian than African-American families, apparently because Caucasian probands were more extreme relative to their population mean. Risk ratios for moderate obesity (BMI ≥ 30) were around 2 for African-Americans and were a little higher in Caucasians. Ratios for extreme obesity (BMI ≥ 40) ranged from 3 to 5 in African-Americans and from about 5 to 9 in Caucasians. Thin relatives were rare in families of both races. Risk ratios appear high enough in both racial groups to facilitate the identification of quantitative trait loci underlying common obesity phenotypes. The high population prevalence of obesity in African-American women will require particularly high selection thresholds to achieve risk ratios comparable to those for Caucasians. The scarcity of thin siblings in both groups will greatly increase the effort required in sample recruitment for discordant pair designs.
Inhibition of Substance-P-Induced Histamine Release from Rat Peritoneal Mast Cells by 8-Methoxypsoralen Plus Long-Wave Ultraviolet Light Irradiation: Decreased Intracellular Calcium as a Possible Mechanism
Authors: Amano Hiroo , Kurosawa Motohiro , Miyachi Yoshiki
Published: April 2003

Rat peritoneal mast cells purified on a Percoll gradient were activated by substance P (SP) and the effect of 8-methoxypsoralen (8-MOP) plus long-wave ultraviolet light (UVA) irradiation (8-MOP/UVA) on SP-induced histamine release from the cells was investigated. At a concentration of 10–5 M SP caused a significant histamine release. 8-MOP or UVA irradiation alone at the doses used in the present study neither induced a histamine release nor had any significant effects on SP-induced histamine release from mast cells. On the other hand, 8-MOP/UVA inhibited SP-induced histamine release; this inhibition was dependent on the UVA doses (0.5–3.0 J/cm2) and was accompanied by a reduction in the rise in intracellular calcium concentrations ([Ca2+]i). These data suggest that 8-MOP/UVA inhibits histamine release from SP-activated rat peritoneal mast cells by suppressing the rise in [Ca2+]i.
Exogenous Nitric Oxide Regulates the Degranulation of Human Basophils and Rat Peritoneal Mast Cells
Authors: Iikura Motoyasu , Takaishi Toshiaki , Hirai Koichi , Yamada Hirokazu , Iida Mariko , Koshino Takeshi , Morita Yutaka
Published: April 2003

This study was designed to investigate whether anti-IgE-induced or ionophore A23187-induced histamine release from human basophils is regulated by exogenous nitric oxide (NO), and to assess some similarities between the effect of NO on basophils and that on rat peritoneal mast cells (RPMC). The NO donor, sodium nitroprusside (SNP), inhibited A23187-induced histamine release from crude human basophils and crude RPMC in a dose-dependent fashion. This downregulation was still observed when SNP was washed out just before the cell stimulation, indicating that the effect of SNP was irreversible. The downregulation disappeared in both purified cell populations after the removal of contaminating cells. However, when purified cells were preincubated with SNP in the presence of 5 mM N-acetylcysteine (NAC), increasing the bioavailability of NO, the downregulation was recovered. The presence of NAC significantly augmented the downregulation of SNP on A23187-induced histamine release from both crude cell populations. In contrast, SNP had no effect on anti-IgE-induced histamine release from either crude or purified basophil preparation in the absence of NAC, and SNP plus NAC inhibited anti-IgE-induced histamine release from both cell preparations. The same results were obtained with crude and purified RPMC preparations under the same conditions. These results show that SNP similarly downregulated exocytosis of basophils and RPMC, and acquired the potent effect in the presence of NAC, indicating that exogenous NO plays a part in the regulation of basophil and mast cell activation.
Effects of Some Anti-Asthma Drugs on Human Eosinophil Superoxide Anions Release and Degranulation
Authors: Ezeamuzie Charles  I. , Al-Hage Mary
Published: April 2003

Background: Eosinophil infiltration of bronchial tissues and subsequent release of inflammatory mediators by them are the hallmarks of bronchial asthma but it has not yet been clarified whether anti-asthma drugs affect these cells directly. In this study, we investigated the direct effects of 8 clinically used anti-asthma drugs [salbutamol, salmeterol, theophylline, denbufylline, disodium cromoglycate (DSCG), azelastine, ketotifen and dexamethasone] on superoxide anions (O–2) and eosinophil peroxidase (EPO) release from human blood eosinophils in vitro. Methods: Highly purified eosinophils were stimulated for O–2 release with platelet-activating factor (PAF) or interleukin-5 (IL-5), while for EPO release complement fragment (C5a) or N-formyl-methionyl-leucyl-phenylalanine (FMLP) was employed. Generated products were assayed by standard techniques. Results: All the drugs, except ketotifen and dexamethasone, inhibited PAF-induced O–2 release in a dose-dependent manner. The IC50 values were 0.7, 5.8, 330, 3,500, 4,200 and 6,250 nM for DSCG, denbufylline, salmeterol, azelastine, salbutamol and theophylline, respectively. On IL-5-induced release, the effects were similar except that salbutamol completely failed to inhibit the release induced by this stimulus. In contrast, EPO release was generally poorly inhibited, especially when the release was induced by C5a. Only theophylline and azelastine (both at 10–4 M or more) were able to inhibit EPO release by both C5a and FMLP. Salbutamol and, to a lesser extent, salmeterol inhibited FMLP-, but not C5a-induced EPO release, while all the other drugs tested were inactive. Conclusions: The results show that some of the anti-asthma drugs, but not all, do exert direct effects on human blood eosinophils but these effects may be stimulus-dependent and by far more pronounced against O–2 release than against degranulation.
Expression of Histamine Receptors in Nasal Epithelial Cells and Endothelial Cells – The Effects of Sex Hormones
Authors: Hamano Nanako , Terada Nobuhisa , Maesako Ken-ichi , Ikeda Tatehiko , Fukuda Setsuya , Wakita Jun , Yamashita Tetsuji , Konno Akiyoshi
Published: April 2003

Background: Hyperreactivity of the nasal mucosa is a characteristic of nasal allergy. During pregnancy, aggravation of nasal allergic symptoms is occasionally observed in subjects with nasal allergy. Methods: Using the reverse transcription-polymerase chain reaction and Southern blot hybridization method, we investigated histamine H1 receptor mRNA (H1R mRNA) expressions in specimens of nasal epithelial layer obtained by scraping, as well as cultured human nasal epithelial cells (HNECs) and human mucosal microvascular endothelial cells (HMMECs). We compared the expressions on the specimens from patients with nasal allergy with those with nonallergic rhinitis or those from normal volunteers. In addition, we investigated the effects of female hormones on the H1R mRNA expressions in HNECs and HMMECs. Results: H1R mRNA was detected in scraped specimens of nasal epithelial layer, as well as in HNECs and HMMECs. The mRNA expressions in nasal mucosal scraped specimens of epithelial layers and HNECs were more marked in patients with nasal allergy than in the other two groups. In addition, the present study demonstrates that the female hormones β-estradiol and progesterone significantly increase the expressions of H1R mRNA on HNECs and HMMECs. Conclusion: The increase of the expressions of H1R mRNA may explain, in part, the nasal hyperreactivity to histamine observed in patients with nasal allergy. It has also been suggested that sex hormones are related to the preponderance of females in the incidence of allergic rhinitis after puberty, and that they are related, at least partially, to the aggravation of the nasal hyperreactivity symptoms during pregnancy through the enhanced expression of H1R mRNA on HNECs and HMMECs.
Induction of Tolerance via the Respiratory Mucosa
Authors: Lowrey Jacqueline A. , Savage Nigel D.  L. , Palliser Deborah , Corsin-Jimenez Marta , Forsyth Lynn M.  G. , Hall Gillian , Lindey Susannah , Stewart Gareth A. , Tan Karen A.  L. , Hoyne Gerard F. , Lamb Jonathan R.
Published: April 2003

Immunological tolerance is defined as a state of specific non-responsiveness to a particular antigen induced by previous exposure to that same antigen. The mucosal surfaces comprise the upper and lower respiratory tracts, the gastrointestinal tract and the urogenitary tract, and are a major site of antigenic challenge. The immune system associated with the mucosa has the extraordinary potential to discriminate between antigens that are harmless (e.g. inhaled and dietary antigens) and those that are associated with pathogens. Normally soluble proteins delivered through the mucosal surfaces do not elicit a strong systemic immune response but instead induce a transient local immune response that is replaced by long-term peripheral unresponsiveness – this is termed mucosal tolerance. The phenomenon of oral tolerance is well established and considerable attention has focussed on defining the underlying mechanisms. However, only comparatively recently was the induction of tolerance via the respiratory mucosa described, and it is this form of mucosal tolerance which forms the basis of this review.
Changes in Blood Leukocyte Distribution during Double-Blind, Placebo-Controlled Food Challenges in Children with Atopic Dermatitis and Suspected Food Allergy
Authors: Beyer Kirsten , Renz Harald , Wahn Ulrich , Niggemann Bodo
Published: April 2003

Background: The development of clinical reactions to food antigens is associated with cellular changes. The aim of this study was to determine whether the clinical outcome of double-blind, placebo-controlled food challenges would correlate with changes in blood leukocyte distribution. Methods: Double-blind, placebo-controlled food challenges were performed in 17 children with atopic dermatitis sensitized to hen’s egg or cow’s milk and in 9 children with atopic dermatitis but not sensitized to food. Blood leukocyte distribution and lymphocyte subsets were determined prior to and 24 h after challenges. Results: In food-sensitized children the numbers of leukocytes and lymphocytes decreased significantly after allergen challenge independent of the clinical outcome of the provocation (p < 0.002 in both cases). This decrease was seen in T (CD3+) and B (CD19+) cell subsets (p < 0.007 and p < 0.0005, respectively). The CD4/CD8 ratio increased (p < 0.04). The number of memory cells (CD45R0) dropped (p < 0.02 for CD4 and p < 0.004 for CD8) and there was a loss of L-selectin (p < 0.003 for CD4 and CD8). No changes in thrombocytes, neutrophils, eosinophils and basophils were observed. None of these changes were seen in the sensitized patients during placebo challenges or in the non-sensitized group of children. Conclusion: Changes in the leukocyte distribution after allergen challenge seem to be associated with sensitization, but not with the clinical outcome of the oral food challenge. They reflect important changes in the immune system in response to allergens, but are not useful in monitoring double-blind, placebo-controlled food challenges.
Seasonal Chronic Cough with Sputum Eosinophilia Caused by Trichosporon cutaneum (Trichosporon asahii)
Authors: Ogawa Haruhiko , Fujimura Masaki , Amaike Shiho , Nishiura Yuriko , Nakagawa-Yoshida Kazuko , Suga Moritaka , Ando Masayuki , Matsuda Tamotsu
Published: April 2003

The case of a 46-year-old man with a chronic cough with sputum eosinophilia (atopic cough) caused by Trichosporon cutaneum serotype II (Trichosporon asahii) is reported. The diagnosis was made with the inhalation challenge test with T. asahii antigen. He was admitted for the diagnosis and treatment of a severe nonproductive cough in the summer season. Although his sputum contained 13% eosinophils of nucleated cells, he did not have bronchial hyperresponsiveness to methacholine or a heightened bronchomotor tone. Bronchodilator therapy was not effective for his cough. His symptoms worsened on returning home, suggesting the existence of some etiologic agent in his house. A high titer of serum anti-Trichosporon antibody was detected and antigen provocation test with the Trichosporon extract was positive: the development of a cough 6 h later and a decrease in the cough threshold to inhaled capsaicin 48 h later (7.85 μM from 31.3 μM prechallenge). This is the first report on a chronic cough with sputum eosinophilia induced by T. cutaneum (T. asahii).
Thunderstorm Asthma Due to Grass Pollen
Authors: Suphioglu Cenk
Published: April 2003

It is widely known and accepted that grass pollen is a major outdoor cause of hay fever. Moreover, grass pollen is also responsible for triggering allergic asthma, gaining impetus as a result of the 1987/1989 Melbourne and 1994 London thunderstorm–associated asthma epidemics. However, grass pollen is too large to gain access into the lower airways to trigger the asthmatic response and micronic particles <5 μm are required to trigger the response. We have successfully shown that ryegrass pollen ruptures upon contact with water, releasing about 700 starch granules which not only contain the major allergen Lol p 5, but have been shown to trigger both in vitro and in vivo IgE–mediated responses. Furthermore, starch granules have been isolated from the Melbourne atmosphere with 50–fold increase following rainfall. Free grass pollen allergen molecules have been recently shown to interact with other particles including diesel exhaust carbon particles, providing a further transport mechanism for allergens to gain access into lower airways. In this review, implication and evidence for grass pollen as a trigger of thunderstorm–associated asthma is presented. Such information is critical and mandatory for patient education and training in their allergen avoidance programs. More importantly, patients with serum IgE to group 5 allergens are at high risk of allergic asthma, especially those not protected by medication. Therefore, a system to determine the total atmospheric allergen load and devising of an effective asthma risk forecast is urgently needed and is subject to current investigation.
Determinants and Mechanisms of Human Immune Responses to Bee Venom Phospholipase A2
Authors: Blaser K. , Carballido J.M. , Faith A. , Crameri R. , Akdis C.A.
Published: April 2003

The elicitation of an immune response to protein antigens depends on the specific recognition of antigenic determinants (epitopes) by T and B lymphocytes. Bee venom phospholipase A2 (PLA) represents the major antigen/allergen of honey bee venom. It displays three dominant immunogenic peptide and one glycopeptide T cell recognition sites. These epitopes are equally recognized by both allergic and nonallergic individuals. A mixture of the three epitope containing peptides was successfully used in specific immunotherapy of bee venom–allergic patients. Both peptide and whole bee venom immunotherapy induced a state of specific anergy in T cells. The production of specific IgE and IgG4 antibodies directly correlated with the secreted interleukin–4:γ–interferon (IL–4:IFNγ) ratio, which itself depended on the concentration of available antigen and the strength of the T cell–activating signal. This signal comprises accumulated molecular interactions delivered by engagement of the antigenic peptide/MHC class II complex with the T cell receptor (TcR). Indeed the thermodynamic laws of chemical equilibrium reactions reveal that the antigen concentration, together with the equilibration constant Ki and the related Gibbs standard free energy ΔG° of the MHC–II/Ag/TcR complex reaction, may govern the secreted IL–4:IFNγ ratio, and in consequence, differential IgE and IgG4 antibody formation. Ki includes epitope and MHC–II haplotype variability and therefore represents a measure of immunological individuality. A major B cell epitope was determined by using point–mutated PLA. Specific antigen recognition by B cells can trigger distinct cytokine profiles in T cells and contribute to the differential regulation of specific IgE and IgG4 antibodies. Our results indicate that distinct cytokine profiles inducing allergic and nonallergic responses can be attributed to thresholds of T cell activation generated by the specific binding properties of individual MHC–II molecules to immunogenic T cell epitopes and their presentation to TcR.
Cellular and Molecular Characterization of a Major Soybean Allergen
Authors: Helm Ricki M. , Cockrell Gael , Herman Eliot , Burks A. Wesley , Sampson Hugh A. , Bannon Gary A.
Published: April 2003

Soybean proteins share a large number of cross–reacting allergens with other members of the legume family; however, soy–allergic patients rarely react clinically to other members of the legume family. Gly m Bd 30K, an IgE–binding protein with a molecular weight of 30 kD, was identified in soybean extracts by Western IgE–immunoblot analysis. This monomeric allergen was shown to have an N–terminal amino acid sequence and amino acid composition identical to that of the seed 34–kD protein, P34, a thiol protease of the papain family. Electron–microscopic immunolocalization of P34 monoclonal antibodies and IgE binding to sections of soybean seeds showed dense staining throughout the vacuolar bodies, localizing the allergens in protein storage vacuoles of seed cotyledons. We used pooled serum from soybean–sensitive patients to determine the linear IgE–specific epitopes in the 34–kD allergen amino acid sequence. B–cell epitope mapping revealed 10 regions of IgE–binding activity using an overlapping peptide strategy of 15–mers offset by 8 amino acids throughout the P34 sequence. Smaller overlapping peptides, 10–mers offset by 2 amino acids, revealed 16 distinct linear epitopes, 9 of which were mapped to the mature protein. No obvious amino acid sequence motifs could be identified by the smaller IgE–binding epitopes. Using individual patient serum, 5 immunodominant epitopes were identified in this allergen.
Evaluation of IgG RAST® FEIA for the Assay of Venom–Specific IgG Antibodies during Venom Immunotherapy
Authors: Meier P. , Müller U.
Published: April 2003

Background: Successful venom immunotherapy (VIT) in Hymenoptera allergy is usually associated with a strong increase in venom–specific serum IgG antibodies (sIgG). Methods: We evaluated a new commercial test for the assay of sIgG (Pharmacia CAP System™ IgG RAST® FEIA; FEIA), in comparison with a conventional ELISA technique. Sera from 40 bee– and 40 Vespula–allergic patients were analyzed by FEIA and ELISA before and 3 months after starting VIT. Results: The correlation between sIgG obtained with the two methods was significant: r = 0.862, p<0.0001 for bee venom (BV), r = 0.861, p<0.0001 for Vespula venom (VV). The geometric mean values obtained with FEIA were higher for both venoms (BV p = 0.03; VV p<0.01). A highly significant increase (p<0.0001) was observed during VIT with both methods. This increase was concordant in 93% of VV– and 90% of BV–treated patients. Intra– and interassay relative coefficients of variation were below 10% for FEIA. Conclusion: IgG RAST FEIA is a reproducible and sensitive method for the assay of venom–specific sIgG.