bluuebunny/crossref_metadata_2025 huggingface dataset:
Psoriasis is associated with a SNP haplotype of the corneodesmosin gene (CDSN)
Authors: Orrù S. , Giuressi E. , Casula M. , Loizedda A. , Murru R. , Mulargia M. , Masala M.V. , Cerimele D. , Zucca M. , Aste N. , Biggio P. , Carcassi C. , Contu L.
Published: March 2003

Abstract:A psoriasis susceptibility locus has been mapped to the HLA region in the proximity of the HLA‐C locus. This critical region also contains the CDSN gene coding for the corneodesmosin protein. In a case–control association study of psoriasis in the Sardinian population, we analyzed the allele distribution of eight intragenic SNPs (positions 619, 767, 1215, 1118, 1236, 1243, 1331, 1593) of the CDSN gene and the six haplotypes that are coded by these SNPs. Our study showed that these CDSN haplotypes are very stable and well‐conserved in the Sardinian population. The CDSN2 haplotype was found to be associated with susceptibility to psoriasis. The association did not depend upon any one of the intragenic SNPs taken separately. At the HLA‐C locus, the Cw6 and Cw7 alleles were dragged along by linkage disequilibrium with the CDSN2 haplotype and only revealed a trend towards association with the disease. Therefore, the intragenic SNPs of the CDSN gene and the HLA‐Cw6 and Cw7 alleles are not directly involved in susceptibility to psoriasis. However, the strong association of the CDSN2 haplotype suggests a possible role for the CDSN gene and its chromosome region in susceptibility to psoriasis.
A MAGE‐A4 peptide presented by HLA‐B37 is recognized on human tumors by cytolytic T lymphocytes
Authors: Zhang Y. , Stroobant V. , Russo V. , Boon T. , Van Der Bruggen P.
Published: March 2003

Abstract: ‘Cancer‐germline’ genes such as those of the MAGE family are expressed in many tumors and in male germline cells, but are silent in normal tissues. They encode shared tumor‐specific antigens, which have been used in therapeutic vaccination trials of cancer patients. MAGE‐A4 is expressed in more than 50% of carcinomas of esophagus, head and neck, lung, and bladder. We report here the identification of a new MAGE‐A4 encoded peptide, which is recognized by a cytolytic T lymphocyte (CTL) clone on HLA‐B*3701. The sequence of the peptide is SESLKMIF. It corresponds to the MAGE‐A4156‐163 protein sequence. When tumor cells expressing MAGE‐A4 were transfected with HLA‐B*3701, they were recognized by the CTL clone, demonstrating that the peptide ought to be processed in tumor cells and could therefore serve as a target for therapeutic antitumoral vaccination.
Role of the Autoimmune Regulator (AIRE) gene in alopecia areata: Strong association of a potentially functional AIRE polymorphism with alopecia universalis
Authors: Tazi‐Ahnini R. , Cork M.J. , Gawkrodger D.J. , Birch M.P. , Wengraf D. , McDonagh A.J.G. , Messenger A.G.
Published: March 2003

Abstract: Alopecia areata is characterized by a reversible form of patchy or complete hair loss associated with T‐cell infiltration of hair follicles. The lifetime disease risk of ∼1.4% in the general population is increased to more than 30% in autoimmune polyendocrinopathy candidiasis ectodermal dysplasia syndrome (APECED), a recessive condition resulting from a mutation of the autoimmune regulator (AIRE) gene on chromosome 21q22.3. Aire protein is thought to have transcriptional regulatory activity but its role is not well defined at present. In this study, we have examined the possible involvement of AIRE in the pathogenesis of alopecia areata.

On screening the AIRE coding sequence, we identified 20 variants. Two of these at positions, G961C and T1029C, give rise to amino acid changes, S278R and V301A, located in the DNA‐binding segment (SAND) and PHD1 zinc finger motif, respectively. We found no difference in the frequency of the AIRE T1029C polymorphism between the control and patient groups. We genotyped 202 alopecia areata patients and 175 matched Caucasian controls for the AIRE G961C alleles. The frequency of the rare allele (961G) was 0.08 in the controls and there was a significant increase to 0.13 in alopecia areata overall and 0.20 in severe disease (alopecia universalis). We found no association between the AIRE G961G variant and mild (patchy) alopecia areata or alopecia totalis. However, the AIRE 961G allele is a potent risk factor (> 3) for the severest form of alopecia areata, and for disease of early age at onset (at 30 years). The change from serine to arginine in the SAND domain of AIRE protein may have a significant effect on AIRE DNA‐binding activity. Moreover, our results could provide a rational explanation of the unusually high frequency of AA in APECED patients, supporting the concept of AA as an autoimmune disease.
Uniquely folded mini‐protein motifs
Authors: Imperiali B. , Ottesen J.J.
Published: March 2003

Abstract: Mini‐proteins containing fewer than 40 amino acids provide simple model systems for studying protein folding and stability as well as serving as scaffolds for the rational design of new functional motifs. This article reviews current progress on the design and characterization of discretely folded mini‐protein motifs.
Structures of the transmembrane helices of the G‐protein coupled receptor, rhodopsin
Authors: Katragadda M. , Chopra A. , Bennett M. , Alderfer J.L. , Yeagle P.L. , Albert A.D.
Published: March 2003

Abstract: An hypothesis is tested that individual peptides corresponding to the transmembrane helices of the membrane protein, rhodopsin, would form helices in solution similar to those in the native protein. Peptides containing the sequences of helices 1, 4 and 5 of rhodopsin were synthesized. Two peptides, with overlapping sequences at their termini, were synthesized to cover each of the helices. The peptides from helix 1 and helix 4 were helical throughout most of their length. The N‐ and C‐termini of all the peptides were disordered and proline caused opening of the helical structure in both helix 1 and helix 4. The peptides from helix 5 were helical in the middle segment of each peptide, with larger disordered regions in the N‐ and C‐termini than for helices 1 and 4. These observations show that there is a strong helical propensity in the amino acid sequences corresponding to the transmembrane domain of this G‐protein coupled receptor. In the case of the peptides from helix 4, it was possible to superimpose the structures of the overlapping sequences to produce a construct covering the whole of the sequence of helix 4 of rhodopsin. As similar superposition for the peptides from helix 1 also produced a construct, but somewhat less successfully because of the disordering in the region of sequence overlap. This latter problem was more severe for helix 5 and therefore a single peptide was synthesized for the entire sequence of this helix, and its structure determined. It proved to be helical throughout. Comparison of all these structures with the recent crystal structure of rhodopsin revealed that the peptide structures mimicked the structures seen in the whole protein. Thus similar studies of peptides may provide useful information on the secondary structure of other transmembrane proteins built around helical bundles.
Synthetic peptides from the N‐domains of CEACAMs activate neutrophils
Authors: Skubitz K.M. , Campbell K.D. , Skubitz A. P. N.
Published: March 2003

Abstract: Four members of the carcinoembryonic antigen family, CEACAM1, CEACAM8, CEACAM6 and CEACAM3, recognized by CD66a, CD66b, CD66c and CD66d monoclonal antibodies (mAb), respectively, are expressed on human neutrophils. CD66a, CD66b, CD66c and CD66d mAb binding to neutrophils triggers an activation signal that regulates the adhesive activity of CD11/CD18, resulting in an increase in neutrophil adhesion to human umbilical vein endothelial cells. Molecular modeling of CEACAM1 using IgG and CD4 as models has been performed, and three peptides from the N‐terminal domain were found to increase neutrophil adhesion to human umbilical vein endothelial cell monolayers. The peptides were 14 amino acids in length and were predicted to be present at loops and turns between β‐sheets. To better understand the amino acid sequences critical for this biological activity, in the present study we examined the other neutrophil CEACAMs and the highly homologous CEACAM, CEA. Molecular modeling of the N‐terminal domains of human CEACAM8, ‐6, ‐3 and CEA was performed. Twenty peptides, each 14 amino acids in length, that were homologous to the previously reported peptides from the N‐domains of CEACAM1, were synthesized and tested for their ability to alter neutrophil adhesion. Only one new peptide, from the N‐domain of CEA, was found to increase neutrophil adhesion, and this peptide differed from the corresponding CEACAM1 peptide by only a single conservative amino acid substitution. Importantly, minor amino acid differences between active and inactive homologous peptides suggest regions of these peptides that are critical for biological activity. The data suggest that the regions SMPF of peptide CD66a‐1, QLFG of peptide CD66a‐2 and NRQIV of peptide CD66a‐3 are critical for the activities of these peptides, and for the native CEACAMs.
Probing degeneracy in antigen–antibody recognition at the immunodominant site of foot‐and‐mouth disease virus
Authors: Gomes P. , Giralt E. , Andreu D. , Ochoa W. , Verdaguer N.
Published: March 2003

Abstract: Antigen−antibody binding is regarded as one of the most representative examples of specific molecular recognition in nature. The simplistic view of antigenic recognition in terms of a lock‐and‐key mechanism is obsolete, as it is evident that both antigens and antibodies are flexible and can undergo substantial mutual adaptation. This flexibility is the source of complexities such as degeneracy and nonadditivity in antigenic recognition. We have used surface plasmon resonance to study the effects of combining multiple amino acid replacements within the sequence of the antigenic GH loop of foot‐and‐mouth disease virus. Our aim was 2‐fold: to explore the extent to which antigenic degeneracy can be extended in this particular case, and to search for potential nonadditive effects in introducing multiple amino acid replacements. Combined analysis of one such multiply substituted peptide by SPR, solution NMR and X‐ray diffraction shows that antigenic degeneracy can be expected as long as residues directly interacting with the paratope are conserved and the peptide bioactive folding is unaltered.
Sequence requirements for the activity of membrane‐active peptides
Authors: Werkmeister J.A. , Hewish D.R. , Kirkpatrick A. , Rivett D.E.
Published: March 2003

Abstract:  Synthetic peptides were constructed with the sequence of the first 20 residues of melittin and terminating with a range of different amino acid amides. These were found to have haemolytic and cytolytic activity similar to that of melittin, provided that certain charge constraints were observed. The nature of the 21st residue was not critical except when the residue introduced a negative charge. The presence of at least two positive charges in the molecule was found to be essential for activity. One of these charges could be the amino‐terminal amine. Peptides could be inactivated by the addition of a non‐acidic presequence which was acetylated at the N‐terminus. Introducing a protease cleavable sequence into an N‐terminal extension of the peptides produced analogues with low haemolytic activity that could be activated by proteolytic action. A peptide with extra positive charges introduced on the hydrophilic face of the helix possessed a haemolytic activity that was greater than that of melittin.
Highly potent p21WAF1‐derived peptide inhibitors of CDK‐mediated pRb phosphorylation: Delineation and structural insight into their interactions with cyclin A
Authors: Zheleva D.I. , McInnes C. , Gavine A.‐L. , Zhelev N.Z. , Fischer P.M. , Lane D.P.
Published: March 2003

Abstract: The tumour suppressor protein p21WAF1 plays a central role in regulating eukaryotic cell‐cycle progression. Through its association with G1‐ and S‐phase CDK complexes it regulates activation of the retinoblastoma protein (pRb) and E2F transcription factors. Recognition of CDK/cyclin complexes by p21 occurs, at least in part, through a protein–protein interaction with a binding groove on the cyclin subunit. The same groove has been shown to be involved in the recruitment of macromolecular CDK substrates, including pRb and E2F. Blocking of this recruitment site therefore prevents recognition and subsequent phosphorylation of CDK substrates and offers a therapeutic approach towards restoration of p21‐like tumour suppression. Starting from the C‐terminal cyclin‐binding domain of p21 we have identified the minimal and optimized bioactive 152HAKRRLIF159 peptide sequence with respect to CDK protein kinase inhibition where pRb is the substrate. The phosphorylation of histone H1, however, which does not contain a recognizable cyclin‐binding motif, was unaffected. Detailed structure−activity relationship investigations revealed that the determinants within this sequence are residues Arg155, Leu157 and Phe159 and more completely define the composition of the cyclin‐binding motif. A marked increase in potency was obtained upon replacement of the native Ser153 with an Ala residue in the context of short synthetic peptide inhibitors and significantly, this mutation resulted in comparable affinity with CDK2/cyclin A as does the full‐length recombinant p21 (which has CDK2 and cyclin A binding sites). Peptides derived from various proteins known to interact with cyclins were compared for potency and selectivity. A molecular model of the complex between the cyclin groove and the HAKRRLIF peptide was constructed. This model accounts for the observed peptide structure−activity relationships, including the potency enhancement of the LIF sequence occupying the hydrophobic pocket. Furthermore, it provides generic insights into molecular interactions governing cyclin groove recognition and lays the foundation for the development of peptidomimetic inhibitors of CDKs.
Regulators of G protein signaling (RGS proteins): Novel central nervous system drug targets
Authors: Neubig R. R.
Published: March 2003

Abstract: Many drugs of abuse signal through receptors that couple to G proteins (GPCRs), so the factors that control GPCR signaling are likely to be important to the understanding of drug abuse. Contributions by the recently identified protein family, regulators of G protein signaling (RGS) to the control of GPCR function are just beginning to be understood. RGS proteins can accelerate the deactivation of G proteins by 1000‐fold and in cell systems they profoundly inhibit signaling by many receptors, including mu‐opioid receptors. Coupled with the known dynamic regulation of RGS protein expression and function, they are of obvious interest in understanding tolerance and dependence mechanisms. Furthermore, drugs that could inhibit their activity could be useful in preventing the development of or in treating drug dependence.
Increased levels of soluble Fcγ receptor III in gingival fluid from periodontal lesions
Authors: Yuan Z.‐N. , Tolo K. , Schenck K. , Helgeland K.
Published: March 2003

Enzyme‐linked immunosorbent assay was used for determination of the concentration of soluble Fcγ receptor III (FcγRIII) in 40 samples of gingival fluid obtained from periodontal pockets in 30 patients with periodontitis. The assay was based on a monoclonal immobilized antibody binding FcγRIII and a polyclonal FcγRIII rabbit antibody for its quantification. The results indicate a substantially increased concentration of soluble FcγRIII in gingival fluid as compared to the serum level. This increased concentration of soluble FcγRIII may interfere with phagocytosis and immune homeostasis in the periodontal lesions.
High prevalence of human papillomaviruses in the normal oral cavity of adults
Authors: Terai M. , Hashimoto K. , Yoda K. , Sata T.
Published: March 2003

Human papillomavirus (HPV) infection in the normal oral cavity was studied by the sensitive polymerase chain reaction (PCR) using primers for the L1 region of human papillomavirus DNA and high fidelity amplification system. Cells were scraped from the oral mucosae of 7 (mean age; 42 years) and 30 (mean age; 32 years) volunteers with and without skin warts, respectively. Human papillomavirus DNA was detected in 30/37 (81.1%) specimens and their copy numbers per cell were 10−1 to 10−4 (mean, 10−3). The human papillomavirus types determined by PCR‐based sequencing analysis were HPV‐18 (26/30; 86.7%), ‐61 (18/30; 60%), ‐59 (7/30; 23.3%), ‐16 (2/30; 6.7%), ‐6 (1/30; 3.3%) and an unknown type (HPV‐X71) (1/30; 3.3%). Multiple human papillomavirus types were present in 17/30 (56.7%specimens. HPV‐6 was detected in 2 of 7 skin warts and differed from the human papillomavirus types of the corresponding oral specimens. These data suggest that human papillomavirus infection in the oral mucosa occurs much more frequently than previously considered.
Phenotypes and randomly amplified polymorphic DNA profiles of Candida albicans isolates from root canal infections in a Finnish population
Authors: Waltimo T. M. T. , Dassanayake R. S. , Ørstavik D. , Haapasalo M. P. P. , Samaranayake L. P.
Published: March 2003

A total of thirty‐seven Candida albicans isolates from root canal infections in a Finnish population were subtyped using phenotypic and genotypic methods. A previously described biotyping method based on the presence of five different enzymes, assimilation of eleven different carbohydrates and boric acid sensitivity of the yeasts was used to determine the phenotype. Commercially available API ZYM and API 20 C test kits were used to determine the presence of enzymes and assimilation of carbohydrates. The sensitivity of the isolates to boric acid was tested by their ability to grow on yeast‐nitrogen‐agar with incorporated boric acid (1.8 mg  ·  ml−1). Combination of the tests revealed a total of 14 different phenotypes. The majority of the isolates, 26 strains, were classifiable into three major phenotypes: 16 isolates (43.2%) belonged to phenotype A1R, six (16.2%) to A1S and four (10.8%) to B1S. The remaining 11 phenotypes represented only a single isolate each. The randomly amplified polymorphic DNA profiles were used to determine the genotypes. For this purpose two different primers, RSD6 and RSD12 were used to develop a combination randomly amplified polymorphic DNA profile for each isolate. Altogether 31 genotypes were noted among the 37 isolates, of which only three pairs of isolates presented with congruent phenotypic and genotypic profiles. The heterogeneity of both the phenotypic and randomly amplified polymorphic DNA profiles of C. albicans isolates from root canal infections is akin to previous reports from other oral and non‐oral sources in different geographic locales.
Oral colonization of aerobic and facultatively anaerobic gram‐negative rods and cocci in irradiated, dentate, xerostomic individuals
Authors: Leung W. K. , Jin L. J. , Yam W. C. , Samaranayake L. P.
Published: March 2003

This study aimed at investigating the oral colonization of aerobic and facultatively anaerobic gram‐negative rods and cocci in head‐ and neck‐irradiated, dentate, xerostomic individuals. Subjects were recruited from a nasopharyngeal carcinoma clinic and were segregated into group A: <60 years (n=25, 48±6 years, 5±5 years post‐irradiation) and group B: ≥60 years (n=8, 67±4 years, 2±2 years post‐irradiation) and were compared with age‐ and sex‐matched normal individuals, group C: <60 years (n=20, 44±12 years) and group D: ≥60 years (n=10, 70±3 years). Selective culture of the oral rinse samples was carried out to isolate, quantify and speciate (using API 20E kit) aerobic and facultatively anaerobic gram‐negative rods and cocci recovery. All test subjects were put under comprehensive oral and preventive care for 3 months, and 12 group A and 5 group B subjects were recalled for reassessment of aerobic and facultatively anaerobic gram‐negative rods and cocci colonization. All identical isolates, pre‐ and post‐hygienic care, were phenotypically (Vitek, Hazelwood, MA and antibiogram profile) and genotypically (pulsed‐field gel electrophoresis) evaluated. The aerobic and facultatively anaerobic gram‐negative rods and cocci isolated from the first round oral rinse samples included: Acinetobacter, Neisseria, Chryseomonas, Flavimonas, Pseudomonas, Citrobacter, Enterobacter, Escherichia, Klebsiella, Flavobacterium and Weeksella species. The aerobic and facultatively anaerobic gram‐negative rods and cocci isolation rate was high for irradiated individuals, and they were 64/25% and 100/80% for groups A/C and B/D, respectively. Recovery of aerobic and facultatively anaerobic gram‐negative rods and cocci and Klebsiella pneumoniae subsp. pneumoniae in oral rinse samples were found to be significantly more prevalent in the irradiated subjects (groups A and B). Enterobacteriaceae were more frequently isolated from oral rinse samples of aged irradiated subjects (group B vs D, P<0.05), where the quantity of Citrobacter freundii (colony‐forming units/ml oral rinse) was also significantly elevated. The isolation rate of aerobic and facultatively anaerobic gram‐negative rods and cocci after hygienic care remained unchanged; 3 of 12 and 3 of 5 of the recalled subjects from groups A and B, respectively, harbored same aerobic and facultatively anaerobic gram‐negative rods and cocci species. However, only two pairs of K. pneumoniae subsp. pneumoniae, sequentially isolated from same patients in group B, were found to be identical by pulsed‐field gel electrophoresis. This may be due to reinfection of the microbes from the same source or permanent colonization. In conclusion, irradiation‐induced xerostomia seems to favor frequent, repeated, transient intraoral colonization of aerobic and facultatively anaerobic gram‐negative rods and cocci.
Distribution of the tetracycline resistance determinant tetQ gene in oral isolates of black‐pigmented anaerobes in Japan
Authors: Okamoto M. , Takano K. , Maeda N.
Published: March 2003

We investigated the distribution of tetracycline resistance determinant tetQ in oral black‐pigmented anaerobes using a polymerase chain reaction (PCR) method. A total of 185 healthy subjects were divided into 3 groups based on subject age: young (6 to 10 years, n=58), middle (11 to 40 years, n=96), and elder (exactly 70 years, n=31). The prevalence of black‐pigmented anaerobes in the gingival sulcus among these groups was 29.3%, 28.2%, and 64.5%, respectively. The prevalence of Prevotella nigrescens among these groups was 22.4%, 15.6%, and 32.3%, respectively, whereas the prevalence of Prevotella intermedia was 1.7%, 4.2%, and 35.5%, respectively. Porphyromonas gingivalis was found only in the elder group (16.1%). The prevalence of the tetQ gene in the black‐pigmented anaerobes‐positive subjects was almost the same among the 3 groups (approximately 30%). The tetQ gene was found in 27.5% (46 of 167) of P. nigrescens isolates, whereas it was found in only 6.4% (3 of 47) of P. intermedia isolates and in none of the 19 P. gingivalis isolates. Restriction endonuclease digestion patterns of the PCR products revealed 83.6% of 49 tetQ‐positive isolates were of subtype A2H2 (AluI type 2, HpaII type 2).
Stress and the periodontal diseases: effects of catecholamines on the growth of periodontal bacteria in vitro
Authors: Roberts A. , Matthews J. B. , Socransky S. S. , Freestone P. P. E. , Williams P. H. , Chapple I. L. C.
Published: March 2003

Microorganisms possess the ability to recognize hormones within the host and utilize them to adapt to their surroundings. Noradrenaline and adrenaline, which are released during human stress responses, may act as environmental cues to alter the growth of individual organisms within subgingival biofilms. The aims of this study were to modify, for anaerobic culture, existing methodology used in determining microorganism catecholamine responses and to investigate the growth responses to noradrenaline and adrenaline of 43 microorganisms found within subgingival microbial complexes. We established initial inocula for each strain using anaerobic culture, re‐inoculated into a minimal serum‐based medium and grown anaerobically at 35°C. We assessed organism growth by optical density (OD600nm) readings, with test and control cultures performed in triplicate. Test cultures were supplemented with 50 μm noradrenaline or 100 μm adrenaline. We observed significant growth effects for supplementation with noradrenaline (20 species responding positively) and adrenaline (27 species responding positively), with differences in growth response observed within bacterial species and within and between microbial complexes. The most pronounced positive growth effects of noradrenaline were demonstrated in Actinomyces naeslundii (+ 49.4%), Actinomyces gerenscseriae (+ 57.2%), Eikenella corrodens (+ 143.3%) and Campylobacter gracilis (+ 79.9%). We also observed inhibitory effects of noradrenaline supplementation for Porphyromonas gingivalis (− 11.9%) and Bacteroides forsythus (− 22.2%). Responses to adrenaline tended to mirror the responses seen with noradrenaline. Individual organisms from different microbial complexes vary in their in vitro growth responses to noradrenaline and adrenaline. Such variation may influence the in vivo composition of the subgingival biofilm in response to stress‐induced changes in local catecholamine levels and play a significant role in the aetiology and pathogenesis of the periodontal diseases.
Gender differences in HLA phenotype frequencies found in German patients with generalized aggressive periodontitis and chronic periodontitis
Authors: Reichert S. , Stein J. , Gautsch A. , Schaller H.‐G. , Machulla H.K. G.
Published: March 2003

HLA antigens have been considered as risk factors for periodontitis. Differences in prevalence and in the extent of attachment loss between males and females have suggested that gender‐dependent HLA deviations could play a role in individual predisposition to periodontitis. The aim of the present study was therefore to investigate the incidence of gender‐dependent HLA associations in 50 patients with generalized aggressive periodontitis (AP) and 102 patients with chronic periodontitis (CP) in comparison to 102 probands without any attachment loss caused by periodontitis. HLA typing was carried out using a microlymphocytotoxic test and a polymerase chain reaction with sequence‐specific primers (PCR‐SSP). Female AP patients showed an increase in the frequency of HLA‐A*68/69 and a decrease in the frequency of DRBblank* (non‐DRB3/4/5*) and DQB1*05‐positive probands. Only in female CP patients was HLA‐DQB1*0303 absent, whereas HLA‐DQB1*06 homozygosity increased significantly. With regard to the (AP + CP) periodontitis group as a whole, the increased frequency of HLA‐DQB1*06 homozygosity in females was similar to the findings obtained in the AP group. Evidently, gender is a confounding variable, which should be considered in further studies of HLA and periodontitis.
Messages from the German Multicentre Allergy Study
Authors: Nickel Renate , Lau Susanne , Niggemann Bodo , Grüber Christoph , Von Mutius Erika , Illi Sabina , Kulig Michael , Wahn Ulrich ,   the MAS Group
Published: March 2003

Several birth cohort studies have been initiated during the past two decades to study environmental and genetic risk factors for atopic dermatitis, asthma and allergic rhinitis. This article summarizes results from the German Multicentre Allergy Study (MAS), which has followed children (initially 1314) from birth (in 1990) to the present time. The effects of immunizations, allergen exposure, early sensitization patterns as well as upper airway infections on the subsequent development of asthma and atopy at school age are described. Furthermore, candidate gene studies of atopic dermatitis and increased total serum IgE levels on chromosomes 5q, 12q and 17q in MAS‐children and their parents are outlined.
Development of immunoglobulin G subclass antibodies to ovalbumin, birch and cat during the first eight years of life in atopic and non‐atopic children
Authors: Jenmalm M.C. , Björkstén B.
Published: March 2003

Immune responses to allergens in young children include both Th1‐ and Th2‐like immunity, which may regulate the secretion of immunoglobulin (Ig) G subclass antibodies differently. The time, route and level of exposure to an allergen may be decisive with regard to whether sensitization or tolerance will ensue. To study this, we investigated the development of IgG subclass antibodies to food and inhalant allergens during childhood. The study group comprised a cohort of 96 children participating in a prospective study. IgG subclass antibodies to ovalbumin, Bet v 1 and cat dander were analyzed at birth, 6 and 18 months and 8 years by ELISA. IgG1 and IgG3 subclass antibodies to ovalbumin peaked at 18 months and then declined up to 8 years of age, whereas antibodies to the inhalant perennial allergen cat, but not the inhalant seasonal allergen birch, increased with age. Exposure to cat and birch tended to be associated with high antibody levels to those allergens, whereas antibody levels to ovalbumin were not related to exposure to egg. The presence of positive skin prick tests and circulating IgE antibodies correlated with high levels of IgG subclass antibody responses to the allergens. Atopic symptoms were associated with high levels of IgG subclass, particularly IgG4, antibodies to the allergens. The difference in antibody levels between atopic and non‐atopic children was most marked at 6 months for ovalbumin. For the seasonal inhalant allergen birch, the difference was apparent from 18 months, whereas a difference in antibody levels to the perennial inhalant allergen cat was already present at 6 months. In conclusion, IgG subclass antibodies to food allergens peak in early infancy and are then down‐regulated, whereas antibodies to the inhalant perennial allergen cat, but not the inhalant seasonal allergen birch, increase with age. Atopy is associated with high levels of IgG subclass, particularly IgG4, antibodies to allergens, supporting a deviation of the immune system towards Th2‐like responses in atopic children.
Snail anaphylaxis during house dust mite immunotherapy
Authors: Peroni Diego G. , Piacentini Giorgio L. , Bodini Alessandro , Boner Attilio L.
Published: March 2003

This study reports a 12‐year‐old girl who developed an anaphylactic reaction following snail ingestion during house dust mite (HDM) immunotherapy treatment. Radioallergosorbent (RAST) inhibition showed cross‐reactivity between the two allergens, leading to consideration of HDM as the sensitizing agent. Children undergoing HDM immunotherapy treatment should be aware of the potential risks of hypersensitivity reactions to invertebrate foods.
Wheezing in early life and asthma at school age: Predictors of symptom persistence
Authors: Csonka Péter , Kaila Minna , Laippala Pekka , Kuusela Anna‐Leena , Ashorn Per
Published: March 2003

Early childhood wheezing is associated with asthma later in life. However, the high spontaneous recovery rate and the lack of firm predictors for persistence of wheezing complicates the development of evidence‐based guidelines for long‐term management of wheezy infants and toddlers. Our aim was to define variables that could be used to identify wheezy individuals younger than 3 years of age who would continue to be symptomatic at school age. The method used was a questionnaire‐based cross‐sectional survey of 2027 randomly chosen, 6–13‐year‐old school children. Altogether 1829 (90%) questionnaires were returned. Emergency medical care had been sought for 186 (10.2%) children for wheezing during the first 3 years of life, and only 17.2% of these children had received similar emergency treatment during the 12 months preceding the survey. The total proportion of children with current asthma at school age was 11.4%. A logistic regression analysis indicated that for the early wheezers, a family history of asthma, an itchy rash or food allergy, and exposure to tobacco smoke at home before the age of 3 years, were all independently associated with symptom persistence until school age. Among all wheezy children younger than 3 years, those who have a history of food allergy, itchy rash, asthma occurrence in a sibling or parent, or are exposed to tobacco smoke during the first years of life are at highest risk for symptom persistence until school age.
Exhaled nitric oxide in healthy children: Variability and a lack of correlation with atopy
Authors: Philipp Latzin , Julia Beck , Matthias Griese
Published: March 2003

Nitric oxide (NO) is a free radical produced by several lung cells via the enzyme nitric oxide synthetase (NOS) and can be easily measured in exhaled air by chemiluminescence analysis. As the iso‐enzyme iNOS may be induced by cytokines and endotoxin, NO is elevated in several chronic inflammatory airway diseases. Prior to using exhaled nitric oxide (eNO) as a non‐invasive marker of airway inflammation in daily routine, the role of possibly influencing factors such as age, time of the day, smoking exposure and intra‐individual variability have to be clarified. NO concentrations were measured in 107 healthy children aged 4–18 years at an expiratory flow of 184 ml/s. Spirometry and a skin‐prick test were performed and a questionnaire on family history of atopy, personal symptoms of atopic disease and smoke exposure was completed. For intra‐individual variability nitric oxide was measured in six children three times daily on 6 consecutive days. Median eNO concentration was 5.7 p.p.b., and increased significantly with age but did not vary with gender. No correlation was found between eNO and smoke exposure, positive skin‐prick test, FEV1, MEF25 and time of the day. There was no circadian rhythm found in the six children measured on 6 consecutive days, but the eNO showed an intra‐individual coefficient of variation of 25.9%. With the help of a two‐compartment model of the lung the alveolar NO concentration was estimated to be 4.1 p.p.b and was shown to be constant with age, whereas the airway part of NO steadily increased with age. When comparing eNO values with standardized measurement techniques, the age of the children and the large intra‐subject coefficient of variation have to be taken into account, whereas in healthy children subject‐specific factors such as atopic history, gender and skin test reactivity did not affect eNO measurement.
Prolidase deficiency with hyperimmunoglobulin E: A case report
Authors: Lopes I. , Marques L. , Neves E. , Silva A. , Taveira M. , Pena R. , Vilarinho L. , Martins E.
Published: March 2003

Prolidase deficiency is a rare, inherited disorder characterized by ulceration of the skin, mental retardation, and massive urinary excretion of imidodipeptides. Most patients also have recurrent infections, an unusual facial appearance, and splenomegaly. We describe a girl presenting with chronic dermatitis, recurrent respiratory tract infections since her first months of life, and facial features characteristic of prolidase deficiency. The diagnosis of prolidase deficiency was made at 4.5 months of age. The immunologic study in this patient showed an extreme and progressive increase of total immunoglobulin E (IgE) in serum (reaching the value of 77,600 IU/l) and defective chemotactic function of the neutrophils. Treatment with a hyper‐proteic diet supplemented with ascorbic acid, manganese chlorite, and topical proline resulted in reduction of the frequency and severity of the infections and significant improvement of the skin lesions. The authors discuss the immunologic alterations and the favorable evolution with treatment in this patient.
Evaluation of a parental training program for the management of childhood atopic dermatitis
Authors: Staab Doris , Von Rueden Ursula , Kehrt Rainer , Erhart Michael , Wenninger Kerstin , Kamtsiuris Panagiotis , Wahn Ulrich
Published: March 2003

Atopic dermatitis (AD) in childhood is a common disease with prevalence rates as high as 20%. Its early onset in infancy and its chronic relapsing course puts a special burden on families. Supporting parents in dealing with the management of AD presents a challenge for physicians. The objective of this study was to determine the effect of a structured parental training program on managing AD in children. Two‐hundred and four families participated in a prospective, randomized controlled trial. Children (5 months to 12 years in age) had suffered from moderate‐to‐severe AD for at least 4 months. They were randomly assigned to either the intervention group or a waiting, control group who could participate in the training program 1 year later. The intervention was an inter‐disciplinary, structured educational program which covered medical, nutritional, and psychological issues in six group sessions of 2 h each. The families were assessed at the beginning of the study and 1 year later. Main outcome measures were: severity of eczema (SCORAD); treatment habits; treatment costs; quality of life; and coping strategies. Significant effects were shown regarding treatment behavior, such as regular use of emollients, use of antiseptics and topical steroids in the event of exacerbation, and a reduction in the use of unconventional therapies. Satisfaction with medical treatment was improved, and rumination as an ineffective coping strategy was reduced. Finally, significant reduction of treatment costs was achieved. We conclude that structured training programs for parents of children with AD is a helpful adjunct to dermatological treatment.
How do Thai children and adolescents describe asthma symptoms?
Authors: Phankingthongkum Suwannee , Daengsuwan Tassalapa , Visitsunthorn Nualanong , Thamlikitkul Visanu , Udompunthuruk Suthipol , Vichyanond Pakit
Published: March 2003

Prevalence of childhood asthma appears to be increasing worldwide. In Thailand, the prevalence of childhood asthma increased from 4.2% to 13% within the past decade. The last epidemiologic survey in Thailand utilized the International Study of Asthma and Allergies in Childhood (ISAAC) phase I questionnaire translated into Thai language. Language in the questionnaire can affect the reliability and validity of results of the survey. The purpose of this study is to determine common Thai wordings actually used by Thai children and adolescents to describe wheeze, chest tightness, shortness of breath and dyspnea. Sixty asthmatic Thai children, aged 9.2–18 years with asthmatic attacks less than 1 yr prior to the study, and 178 age‐matched controls were recruited into the study. Asthmatic children spontaneously expressed their terms describing their asthma symptoms (in Thai) and then answered a preoutlined questionnaire regarding asthma terminology during an interview session after viewing the severe attack scene of the International ISAAC video questionnaire. Controls responded only to the preoutlined questionnaire after viewing the video scene. Of the 60 asthmatic children (38 males and 22 females, mean age 11.9 yr), 75% had their last asthmatic attacks within 2 months prior to the study. Wheeze was referred to as ‘’ and ‘/wi:d/’ in 50% and 33% of patients, respectively, and ‘’ in 93.8% among controls. Using only the word ‘/wi:d/’ in our previous ISAAC‐I survey, as it sounded like the English word ‘wheeze’, it appears that up to 67% of the cases could have been missed. Dyspnea was referred to as rapid breathing and feeling tired in 78.2% of cases and as rapid and difficult breathing in 76.3% of controls. Chest tightness was referred to as chest discomfort in 65.7%. Shortness of breath was referred to as not being able to catch a breath, too short a breath, not enough breath and feeling suffocated in 88.8%. Local terms for asthma symptoms should be established and validated into each language to obtain reliable epidemiologic data.
A 500‐ml plastic bottle: An effective spacer for children with asthma
Authors: Zar Heather J. , Asmus Michael J. , Weinberg Eugene G.
Published: March 2003

Inhaled therapy using a metered‐dose inhaler (MDI) with attached spacer has been increasingly recognized as the optimal method for delivering asthma medication for acute attacks and chronic prophylaxis. However, in developing countries the cost and availability of commercially produced spacers limit the use of MDI‐spacer delivery systems. A 500‐ml plastic bottle has been recently adapted to function as a spacer. This article reviews the current data on the efficacy of this bottle‐spacer and discusses its advantages and limitations. It is concluded that a modified 500‐ml plastic bottle is an effective spacer; modification and use of this device should be incorporated into international guidelines for the management of children with asthma.
The prevalence of mouse allergen in inner‐city homes
Authors: Stelmach Iwona , Jerzynska Joanna , Stelmach Wlodzimierz , Majak Pawe , Chew Ginger , Kuna Piotr
Published: March 2003

Mouse allergen has not been studied in detail in the general population. It is common for patients from inner‐city environments to report significant mouse infestation in their homes and neighborhoods. The aim of this study was to determine the prevalence of mouse allergen in the homes of inner‐city children with asthma in relation to the demographic features of these children and their specific housing characteristics. Seventy‐eight dust samples from 39 inner‐city homes of Lodz, Poland, were analyzed for mouse allergen. Skin‐prick tests (SPTs) to mouse allergen were performed in all patients. In addition, data regarding the demographics and housing of the subjects were related to the mouse allergen levels. Mouse allergen was detected in 22 of 78 dust samples (28%), and in 18 of 39 homes (46%), including 13 kitchen (33%) and nine bedroom (23%) samples. Mouse allergen levels did not correlate between different rooms in the same home. The levels detected ranged from 0.09 to 2.34 µg/g of dust. The highest levels were found in kitchens, with median levels of 0.2 µg/g, 95% confidence interval (CI): 0.12–0.85 (range: 0.1–2.34 µg/g); in bedrooms the mean levels were 0.23 µg/g, 95% CI: 0.1–0.97 (range: 0.09–1.62 µg/g). Eleven of 18 children with detectable mouse allergen in house dust, and three of 21 without detectable mouse allergen in house dust, had a positive SPT to mouse allergen. On home inspection, 18% of the homes had evidence of mice in one or two rooms and had higher levels of mouse allergen (p < 0.01). None of the other subject or housing variables evaluated were associated with higher mouse allergen levels. In Polish children, mouse allergen is an important factor of sensitivity and should be recognized in the diagnosis of allergic diseases as well as in allergen‐reduction programmes.
Bilateral nephrectomy, peritoneal dialysis and subsequent cadaveric renal transplantation for treatment of renal failure due to polycystic kidney disease requiring continuous ventilation
Authors: Spechtenhauser B. , Hochleitner B. W. , Ellemunter H. , Simma B. , Hörmann CH. , Königsrainer A. , Margreiter R.
Published: March 2003

Abstract:We report here on a newborn with end‐stage renal failure due to autosomal recessive polycystic kidney disease, also causing ventilation‐requiring respiratory distress. Peritoneal dialysis was able to keep the newborn alive but not wean it from the respirator. After removal of both huge kidneys, dialysis became more effective and allowed the neonate to be extubated only 5 days later. It was decided to register the baby for a pediatric cadaveric kidney transplant when it reached 6 kg/body wt or to perform a living related transplant if no such kidney became available and the baby grew to 7 kg/body wt. At the age of 9 months and a weight of 6 kg a cadaveric kidney from a 20‐month‐old donor became available and was transplanted extraperitoneally. Prophylactic immunosuppression included cyclosporin, mycophenolate mofetil and steroids. Pneumonia on post‐operative day 10 required respiratory care for several days and acute rejection requiring peritoneal dialysis. Both complications were controlled with antibiotics and conversion from cyclosporin to tacrolimus and a temporary increase in steroids. Thirteen months later the child is alive and well with a serum creatinine of 0.6 mg%. From this experience we would recommend early removal of both polycystic kidneys causing end‐stage renal failure and respiratory insufficiency, starting peritoneal dialysis and performing a renal transplant as soon as possible. This therapeutic strategy seems appropriate for this complex situation.
Sandimmune®to neoral®conversion and value of abbreviated AUC monitoring in stable pediatric kidney transplant recipients
Authors: Kelles Annemarie , Herman Jean , Budya Tjandra‐Maga T. , Van Damme‐Lombaerts Rita
Published: March 2003

Abstract:Neoral®is a new microemulsion formulation of cyclosporin A (CsA) that has been reported to have better absorption characteristics than sandimmune®. We converted 25 long‐term pediatric renal transplant recipients with a mean age of 14.1 yr and a mean follow‐up period of 6.4 yr from sandimmune (SIM) to neoral (NEO) on a 1 : 1 basis. The mean dosage of SIM or NEO required to maintain ‘therapeutic range’ steady‐state trough levels between 100 and 200 ng/mL was similar. We compared 6‐h CsA pharmacokinetic profiles taken approximately 6 months after the conversion to NEO with the previous SIM profiles of the same patients. Generally, in the NEO profiles the time to reach the maximum concentration was shorter and the maximum concentration was higher, showing a rapid decline towards the trough‐level when compared to the previous SIM profiles. During intake of NEO the AUC0–12 hin the 12‐h profiles correlates strongly with the AUC0–6 hin the 6‐h profiles (r = 0.98), a similar finding to that which we reported previously for SIM. The median AUC0–6 hfor NEO demonstrates a 70% increase compared to the median AUC0–6 hfor SIM. Despite the increased drug exposure NEO was well tolerated and did not cause any apparent toxicity within the first 6 months after conversion. The CsA blood level 2 h after intake of NEO showed a higher correlation with the AUC0–12 h(r = 0.91) than the trough level (r = 0.64). The abbreviated profile based on three early sampling points and calculated by AUCPRED= 335.9 + 1.1*(C1) + 1.1*(C2) + 5.4*(C4) correlated well with the full AUC (r2 = 0.98, p < 0.0001). Mean prediction error (±SD) was 0.16% (±4.32), and in no patients did the calculated values fall outside the 10% prediction error limit. We therefore conclude that NEO exhibits a higher bioavailability in children compared to SIM without causing apparent toxicity. Monitoring of the C2might be a better alternative for trough level monitoring in daily clinical practice. A strategy of three early sampling points (C1, C2and C4) allows a reliable AUC0–12 hprediction and can reduce the length of observation, making it a useful and cost‐effective tool in clinical practice.
Paecilomyces variotii in a pediatric patient with lung transplantation
Authors: Das Aninda , MacLaughlin Eithne F. , Ross Lawrence A. , Monforte Hector L. , Horn Monica V. , Lam Gennie L. J. , Mason Wilbert H.
Published: March 2003

Abstract: Aspergillus has been noted to be the most common species of filamentous fungus isolated from the airways of lung transplantation (Tx) patients. In general, the bronchi are colonized asymptomatically with Aspergillus but this places such a patient population at greater risk of invasive infection. Other filamentous fungal species may also assume importance in this patient population. Here we report the post‐transplant isolation of Paecilomyces variotii from the airways of a pediatric patient with cystic fibrosis (CF) who underwent bilateral living‐donor lobar lung Tx. This is the first report of isolation of P. variotii in the pediatric lung Tx population. The isolation of filamentous fungi, such as Paecilomyces, with variable in vitro susceptibility to currently available antifungal agents further complicates the approach to post‐transplant antifungal therapy in patients with lung Tx.