bluuebunny/crossref_metadata_2025 huggingface dataset:
A MODERN ANALYSIS OF THE BARYON SPECTRUM
Authors: Dytman Steven A.
Published: March 2003

Although the study of the baryon spectrum has been underway for many years, there is still much room for progress. There are advantages over mesons because most data has 3 or few particles in the final state and the states are largely reached through the s channel. Nevertheless, states have significant overlap and methods to extract their properties are nontrivial. We propose some significant changes to the baryon spectrum as a result recent work with the CMB model.
BRIDGE THE GAP BETWEEN THE LORENZ SYSTEM AND THE CHEN SYSTEM
Authors: LÜ JINHU , CHEN GUANRONG , CHENG DAIZHAN , CELIKOVSKY SERGEJ
Published: March 2003

This paper introduces a unified chaotic system that contains the Lorenz and the Chen systems as two dual systems at the two extremes of its parameter spectrum. The new system represents the continued transition from the Lorenz to the Chen system and is chaotic over the entire spectrum of the key system parameter. Dynamical behaviors of the unified system are investigated in somewhat detail.
Linear Order and Constituency
Authors: Phillips Colin
Published: March 2003

This article presents a series of arguments that syntactic structures are built incrementally, in a strict left-to-right order. By assuming incremental structure building it becomes possible to explain the differences in the range of constituents available to different diagnostics of constituency, including movement, ellipsis, coordination, scope, and binding. In an incremental derivation structure building creates new constituents, and in doing so it may destroy existing constituents. The article presents detailed evidence for the prediction of incremental grammar that a syntactic process may refer only to those constituents that are present at the point in the derivation when the process applies.
Successive-Cyclic Movement and Island Repair: The Difference between Sluicing and VP-Ellipsis
Authors: Fox Danny , Lasnik Howard
Published: March 2003

It is well known that in sluicing constructions wh-dependencies can cross certain projections that are otherwise barriers to movement (Ross 1969, Chomsky 1972). This fact would follow under the assumption that the relevant barriers are somehow deactivated when phonologically deleted (“island repair”). The problem, however, is that another form of phonological deletion (VP-ellipsis; VPE) seems to be impossible in certain contexts where sluicing allows for island repair (Chung, Ladusaw, and McCloskey 1995, Merchant 2001).

Nevertheless, we argue against the conclusion that island repair is a special property of sluicing. The argument is based on two observations. First, the difference between sluicing and VPE seems too broad to warrant the conclusion that island repair is the distinguishing factor (Lasnik 2001). Second, the conclusion is directly refuted by other VPE environments where island repair is possible (Kennedy and Merchant 2000; Fox, in preparation). The argument leaves us with a puzzle that we attempt to resolve while still maintaining the null hypothesis that VPE and sluicing involve the same operation of deletion, differing only in the size of the deleted constituent. Our proposed resolution capitalizes on a special property of the relevant sluicing contexts—namely, the presence of an indefinite NP in the antecedent clause in a position parallel to that of a trace in the elided clause. We argue that given the parallelism conditions on ellipsis, this fact prevents the wh-phrase in the elided clause from undergoing successive-cyclic movement. The remaining option (one-fell-swoop movement) requires the deletion of all barriers, including those that would otherwise be circumvented via an intermediate landing site. Such deletion occurs in sluicing but not in VPE, which targets a smaller constituent.
Fire exit is a potential four transmembrane protein expressed in developing Drosophila glia
Authors: With Sheila , Rice Tiffany , Salinas Claudia , Auld Vanessa
Published: March 2003

Summary: Glia from many diverse organisms play a number of important roles during the development of the nervous system. Therefore, knowing the molecules that control glial cell function will further our understanding of the mechanisms that control nervous system development. We have isolated a novel gene in Drosophila melanogaster that is expressed in a subset of the peripheral glia. We call this gene “Fire exit” (Fie), as the glia that express this gene do so during a time when they mark the entry and exit point of axons at the CNS/PNS boundary. This subset of peripheral glia act as intermediate targets during pathfinding and migration of the sensory axons in particular. Fire exit has been cloned and found to encode a novel transmembrane protein. Fire exit belongs to a group of proteins identified in the Drosophila melanogaster and Anopheles gambiae databases which contain four predicted transmembrane domains and a shared intracellular motif. Mutations that remove the fire exit protein have no obvious disruption to glial function. On the other hand, glia expressing the Fire exit gene bridge the transition zone between CNS and PNS and play a role in sensory axon guidance. Therefore, it appears that, while the glia that express this protein mediate axon guidance, Fire exit itself plays a nonessential part in this function. A role for Fire exit in glial development may be suggested by its evolutionary relationship to a family of lysosome‐associated proteins called LAPTMs and suggests that Fire exit may function in intracellular transport during glial development. genesis 35:143–152, 2003. © 2003 Wiley‐Liss, Inc.
New prognostic indicator for non‐small‐cell lung cancer, quantitation of thymidylate synthase by real‐time reverse transcription polymerase chain reaction
Authors: Shintani Yasushi , Ohta Mitsunori , Hirabayashi Hirohisa , Tanaka Hisaichi , Iuchi Keiji , Nakagawa Katsuhiro , Maeda Hajime , Kido Tetsuo , Miyoshi Shinichiro , Matsuda Hikaru
Published: March 2003

Thymidylate synthase (TS) is an enzyme that catalyzes an important DNA biosynthesis process. The gene expression of TS has not been reported in non‐small‐cell lung cancer (NSCLC) patients. To clarify the correlation between TS mRNA levels and clinicopathological features of NSCLC, we examined 70 Stage I and II NSCLC patients for intra‐tumoral expression of TS using TaqMan reverse transcription polymerase chain reaction (RT‐PCR) assay and immunohistochemistry methods. We also investigated the TS promoter 28 bp polymorphism in 48 cancer tissues using PCR amplification of genomic DNA. Lung cancer tissue showed higher TS mRNA levels than normal lung tissue (Mann‐Whitney U‐tests; p = 0.0020). Further, TS mRNA expression was correlated with immunohistochemical TS expression (p = 0.029). We obtained 2 different DNA fragments, which indicated triple‐repeat (3R) and double‐repeat (2R) type alleles. Cancer tissues with the 3R/3R genotype showed significantly higher TS mRNA levels as compared to those with other genotypes (p = 0.0019). The TS genotype was also correlated with immunohistochemical TS expression (χ2 test; p = 0.0079). The disease‐free survival of the low TS mRNA level group was significantly better than those with high TS mRNA levels (log‐rank test; p = 0.010), however, there were no significant differences found by immunohistochemical evaluation (p = 0.34) or TS genotype analysis (p = 0.11). A multivariate analysis revealed that high TS mRNA levels independently contributed to disease‐free survival. The quantitation of TS mRNA levels is clinically more sensitive and useful for determining the prognosis of Stage I and II NSCLC patients than an immunohistochemical evaluation. © 2003 Wiley‐Liss, Inc.
HLA‐DRB1*01 and DRB1*04 alleles in Sardinian rheumatoid arthritis patients
Authors: Carcassi C. , Passiu G. , Lai S. , Sanna G. , Cauli A. , Alba F. , Mathieu A. , Contu L.
Published: March 2003

In Sardinia, like in other Caucasoid populations, rheumatoid arthritis (RA) is significantly associated with HLA‐DR4 and DR1 antigens. To discover which DR4 and DR1 alleles were associated with the disease we selected 22 Sardinian patients affected by RA. Fifty DR4+ and 28 DR1+ healthy individuals coming from the same geographical area were used as controls. In the Sardinian patients only two DRB1*04 alleles were observed: DRB1*0405 in 11 and DRB1*0403 in three patients. The DRB1*0102 allele was observed in two patients and DRB1*0101 in six patients. Hereditary predisposition to RA in Sardinia therefore seems to be almost exclusively associated with the DRB1*0405 and DRB1*0101 alleles which share the 67LLEQRRAA74–85VG86 epitope in the peptide binding groove.
Identification of DRB alleles in rhesus monkeys using polymerase chain reaction‐sequence‐specific primers (PCR‐SSP) amplification
Authors: Lobashevsky A. , Smith J.P. , Kasten‐Jolly J. , Horton H. , Knapp L. , Bontrop R.E. , Watkins D. , Thomas J.
Published: March 2003

Major histocompatibility complex (MHC) class II molecules play a vital role in the regulation of T‐cell functions in the mammalian immune system. Two key features characterize the polymorphism of MHC haplotypes in humans and non‐human primates: the existence of a large number of alleles, and the high degree of genetic diversity between those alleles. Rhesus monkeys and Chimpanzees have been extensively used as relevant models for human diseases and transplantation We have investigated DRB genes in 19 macaques, members of 3 families, using polymerase chain reaction with sequence‐specific primers (PCR‐SSP) and denaturing gradient gel electrophoresis (DGGE). After amplification PCR products were purified and subjected direct sequencing. Seven animals (Madison #1) were typed by DDGE also. We report that the DRB haplotypes defined by PCR‐SSP exhibit a high degree of concordance with the data obtained by DGGE and direct sequening. Our data show prominent variability in the number of DRB1 alleles ranging from 1–4 per genotype within these families. This analysis demonstrated that most of the amplicons were identical to Mamu‐DRB alleles that our PCR primers were to amplify. However, 98–99% similarity was noticed in the case of Mamu‐DRB1*0303, Mamu‐DRB6*0103 and Mamu‐DRB*W201 alleles. The observed mismatches were located in non‐polymorphic regions. Thus, family studies in rhesus macaques performed by molecular methods confirmed the multiplicity of Mamu‐DRB1 alleles per haplotype and the existence of allelic associations published earlier. In addition, we propose 3 more DRB allele associations (haplotypes): Mamu‐DRB1*04‐DRB5*03; Mamu‐DRB1*04‐*DRB*W5; Mamu‐DRB1*04*W2. The proposed medium‐resolution PCR‐SSP technique appears to be a highly reproducible and discriminatory typing method for detecting polymorphisms of DRB genes in rhesus monkeys.
HLA‐DRB1*04 and susceptibility to type 1 diabetes mellitus in a German/Belgian family and German case‐control study
Authors: Donner H. , Seidl C. , Van der Auwera B. , Braun J. , Siegmund T. , Herwig J. , Weets I. ,   The Belgian Diabetes Registry, Usadel K.H. , Badenhoop K.
Published: March 2003

HLA‐DR4 is a primary disease association marker in type 1 diabetes mellitus (IDDM). We therefore analyzed the transmission of 228 DR4+ haplotypes in 183 families with an IDDM proband (95 from Germany and 88 from Belgium). In a separate case‐control data set, we investigated the HLA‐DRB1*04 and DQ allele distribution in 245 IDDM patients and 177 controls from Germany, all DR4 positive. HLA‐DRB1*0401 and *0402 linked to DQB1*0302 were significantly more often transmitted to patients in the studied families (81% and 89%) in contrast to DRB1*0401‐DQB1*0301 (33%). The case‐control study of HLA‐DQB1*0302+ individuals revealed ‐DRB1*0405 to be more frequent in patients with IDDM and HLA‐DRB1*0403 and ‐DRB1*0404 to be less frequent. HLA‐DQA1*0102‐DQB1*0602 and ‐DQA1*0501‐DQB1*0301 in trans complementation with DRB1*0401‐DQB1*0302 were also significantly less frequent in IDDM patients (P<3×10−7 and P<0.02). In conclusion, HLA‐DRB1*0403 and ‐DQB1*0301 alleles in cis as well as protective DQ haplotypes in trans, confer dominant protection against IDDM in a German / Belgian population.
A novel variant of the MHC‐linked hsp70, hsp70‐hom, is associated with rheumatoid arthritis
Authors: Jenkins S.C. , March R.E. , Campbell R.D. , Milner C.M.
Published: March 2003

The three major histocompatibility complex (MHC)‐linked hsp70s have been screened for variation in their 28 kDa C‐terminal regions by direct nucleotide sequencing of the corresponding DNA fragments. No amino acid variation was detected in the major heat‐inducible hsp70 (encoded by hsp70–1 and hsp70–2), although previously unreported silent mutations were identified in all three of the MHC‐linked hsp70 genes. A novel coding polymorphism, a G to A transition, was identified at nucleotide 2763 of hsp70‐hom (hom‐2763). This dimorphism results in a glutamic acid to lysine alteration at position 602 in the C‐terminal domain of hsp70‐hom. The frequencies of the A‐2763 and G‐2763 alleles were calculated to be 27% and 73%, respectively. The hom‐2763 dimorphism was characterised in 81 HLA‐homozygous cell lines using an ARMS‐PCR assay and A‐2763 was found to be in strong linkage disequilibrium with DRB1*04 (Pc=1.31×10−7, following Bonferoni’s correction). Analysis of 60 rheumatoid arthritis (RA) families, each with an affected sib‐pair, revealed an association between hsp70‐hom A‐2763 and RA using both the transmission disequilibrium test (TDT) and the transmission to sib‐pair (Tsp) test (P=0.0038 and P=0.013, respectively). This association may be due to linkage disequilibrium with HLA‐DR alleles, but could represent an additional risk factor for RA in the MHC class III region.
Association of soluble HLA‐G plasma levels with HLA‐G alleles
Authors: Rebmann V. , Van Der Ven K. , Päßler M. , Pfeiffer K. , Krebs D. , Grosse‐Wilde H.
Published: March 2003

Soluble HLA‐G (sHLA‐G) molecules are found in the peripheral blood of healthy females and males, in cord blood and in amniotic fluids and discussed to be a mediator in maternal‐fetal tolerance. In this study we investigated whether there are allele‐specific differences in expression of sHLA‐G molecules. For this, the sHLA‐G plasma concentrations of 94 healthy unrelated individuals were measured by ELISA and correlated to their HLA‐G genotypes, as determined by sequence analysis of exon 2 and 3 of the HLA‐G gene. Mean sHLA‐G levels in individuals with the most common HLA‐G alleles G*01011 (27.0±2.1 SEM ng/ml, n=66), G*01012 (28.4±3.2 SEM ng/ml, n=34) were very similar. In contrast, individuals carrying the HLA‐G*01013 (8.1±1.7 SEM ng/ml, n=17) or the “null” allele HLA‐G*0105N (8.2±3.2 SEM ng/ml, n=7) presented significantly (Pc=0.001 and Pc<0.01, resp.) reduced sHLA‐G levels. Furthermore, individuals with the HLA‐G*01041 allele had significantly (Pc=0.004) increased sHLA‐G levels (42.5±4.6 SEM ng/ml, n=14). These results demonstrate that the generation of sHLA‐G molecules is associated to certain HLA‐G alleles and imply that sHLA‐G levels are under genetic control. As low and high sHLA‐G plasma levels did not segregate with HLA haplotypes including the HLA‐G*01013 or *01041 allele, additional mechanisms may be involved in the regulation of the individual sHLA‐G levels. Nevertheless, the existence of “low” and “high secretor” HLA‐G alleles further suggests different levels of functionality in immune regulation.
XENOTRANSPLANTATION: A VIEW TO THE PAST AND AN UNREALIZED PROMISE TO THE FUTURE
Authors: Toledo‐Pereyra LH , Lopez‐Neblina F
Published: March 2003

Since the early 20th Century when Emerich Ullman transplanted a pig kidney into the arm of a woman (1902), Princeteau implanted portions of a rabbit kidney into the kidney of a child who was dying of renal insufficiency (1905), Jaboulay transplanted two kidneys from a pig and a goat as donor sources (1906), and Unger implanted a monkey kidney into a human (1910), xenotransplantation has made some strides, mostly related to advanced surgical techniques, improved knowledge of immunological principles, and to steps associated with the development of the most effective immunosuppressive therapy.

Innovative surgical techniques were introduced by Alexis Carrel in the first decade of the 1900s, so that vascular anastomoses could be realized without a considerable amount of thrombotic/embolic problems, long before heparin times. Inasmuch as these advances were soundly characterized, it became evident that the results were far from expected and that the time was not ripe for xenotransplantation.

It took a further 50 years (1963) before Keith Reemtsma transplanted 13 kidneys from chimpanzees into patients with kidney failure. Remarkably, one patient survived for 9 months before dying from an electrolyte imbalance. In the ensuing years, Starzl (1964), Hardy (1964), Cooley (1968), Ross (1968), Barnard (1977), Bailey (1984) and a few others entered this new field with less than satisfactory accomplishments.7The unsolvable barrier of hyperacute rejection required persistence and ingenuity. The recognition of xenoantibodies and their requirement for full depletion, through ex vivo porcine perfusion, plasmapheresis, immunoabsorption and complement inhibition, facilitated important advances in this field. The introduction of accommodation and molecular chimerism has further improved the knowledge of this newly conceived field. Advanced molecular engineering techniques have recently permitted the creation of the clonal Gal‐deficient pig by eliminating the α‐1, 3 galactosyltransferase gene. These discoveries together with better immunosuppression raise hope for the yet unrealized promise of xenotransplantation.
THE UNKNOWN MAN OF ALEXIS CARREL: THE FATHER OF TRANSPLANTATION
Authors: Toledo‐Pereyra LH
Published: March 2003

The contributions and great advances accomplished by the dedicated work and extraordinary genius of Alexis Carrel (1873–1944) made possible the establishment of a new discipline, now considered to be transplantation. His pioneering Nobel Prize winning vessel suturing work (1912) plowed the way for an enhanced participation of surgical leaders in the demonstration of the feasibility of his newly introduced techniques. Even though most of the scientific disciplines associated with transplantation were in their infancy, the possibility of offering a means to realize the surgical face of transplantation presented an optimistic and new horizon for the developing field.

Carrel remains an unknown man to the scientific and nonacademic readers of his life. In addition to his professional and well‐advanced scientific works, he was a mystical individual. He profoundly studied the human being, and through these studies he revealed himself. As one starts to unfold his complex personality through all his nonmedical writings, one begins to encounter the meticulous man, the impatient individual, the religious believer, the truth seeker and, paradoxically, the acceptor of clairvoyance and the supernatural. His popular and the best‐selling book of his times, Man The Unknown (1935), defined Carrel's philosophical principles of life and confirmed his intense interest in discovering man and the most important part of him, the unknown element. For Carrel, man was as complex as he believed himself to be: the unknown man.

Scientists did not take Carrel's philosophical incursions kindly. They did not accept his views and criticized him in all his nonscientific developments. Carrel nevertheless characteristically disregarded his critics and charged himself to search for new concepts and forthcoming ideas. He maintained this resilience through all his existence and his work defines the Carrel as the complex man he was, as the spiritual student he attempted to be, and as the philosopher of the human race he so desired to be in his writings.
HLA PROFILE OF ETHNIC PAKISTANI POPULATION GROUPS
Authors: Zafar MN , Zaidi Y , Ahmed N , Abbas K , Naqvi SAA , Rizvi SAH
Published: March 2003

Class 1 HLA‐A and ‐B and Class 2 HLA‐DR allele frequencies were determined in Pakistani ethnic linguistic population groups. A total of 942 potential kidney donors for living‐related transplants were tested by Collaborative Transplant Study (CTS) 120 antisera trays for HLA‐A and ‐B. All subjects homozygous for an allele, showing weak reactions or with crossreactions were retested by PCR‐SSP using CTS primers, 24 for HLA‐A and 48 for HLA‐B. Class 2 HLA‐DR were determined only by PCR–SSP with 24 primers from the CTS. The common antigen frequencies for HLA‐A were A1=0.312, A2=0.402, A11=0.312, A24=0.221, A26=0.178 and A19, and splits=0.296. At HLA‐B the common alleles were B8=0.234, B 35=0.213, B44=0.145, B51=0.197 and B60=0.177. Common HLA‐DR alleles were DR 2=0.382, DR3(17)=0.424, DR5(11)=0.185, DR 6(13)=0.180 and DR 7=0.240. These results provide baseline data for ethnic Pakistani population groups based on DNA methods. This will help in studies relating to disease associations and cadaveric organ allocation programmes.
HLA class II haplotypes associated with pulmonary interstitial lesions of polymyositis/dermatomyositis in Japanese patients
Authors: Horiki T. , Ichikawa Y. , Moriuchi J. , Hoshina Y. , Yamada C. , Wakabayashi T. , Jackson K. , Inoko H.
Published: March 2003

Abstract: To elucidate the immunogenetic background of idiopathic inflammatory myopathies (IIM) such as polymyositis (PM), dermatomyositis (DM) and any overlapping subsets, with other collagen vascular diseases, HLA class I antigens and class II alleles were determined and compared from individuals with various clinical and serological features of IIM, including pulmonary interstitial lesions (PI). Seventy‐three Japanese patients with myositis (32 PM, 18 DM, 23 overlapped subsets) and 62 healthy unrelated controls were enrolled onto the study. Statistical differences between groups were determined by the Fisher's exact probability test. Serum fluorescent antinuclear antibody, rheumatoid factor (RF), anti‐SS‐A/Ro antibody, anti‐Jo1 antibody and anti‐U1 RNP antibody were examined using routine methods. PI was detected by chest X‐ray and/or computed tomography. In patients with DM, the frequency of the HLA‐DRB1*1302‐DQA1*0102‐DQB1*0604 haplotype was significantly higher than in the healthy controls (42.1% vs 17.7%), and in the patients with PM (42.1% vs 9.4%). Furthermore, the frequency of the HLA‐DRB1*0405‐DQA1*03‐DQB1*0401 haplotype was higher in the PM patients with PI than in the controls (50.0% vs 17.7%), and PM without PI (50.0% vs 5.5%). These results suggest that in terms of HLA class II association, Japanese DM and PM, and PM with and without PI, belong to different clinical groups.
Triplet repeat polymorphism in the transmembrane region of the MICA gene in celiac disease
Authors: Fernandez L. , Fernandez‐Arquero M. , Gual L. , Lazaro F. , Maluenda C. , Polanco I. , Figueredo M. A. , De la Concha E. G.
Published: March 2003

Abstract: Celiac disease (CD) is characterized by a striking expansion of γδT cells in the intestine. These cells interact with MICA, a cell surface protein encoded by a major histocompatibility complex gene. We investigated whether MICA gene polymorphism could contribute to susceptibility to CD. DNA typing for HLA‐DR, DQA1, DQB1, TNF‐308, TNFa, TNFb and a triplet repeat polymorphism in the transmembrane region of the MICA gene were carried out. We performed case–control stratified association studies and transmission disequilibrium tests. Our results indicate that although there is no primary association between MICA polymorphism and CD, there is, in addition to HLA‐DQ, a second susceptibility locus on the 8.1 ancestral haplotype in strong linkage disequilibrium with MICA A5.1 allele.
Molecular analysis of HLA‐DRB1, DQA1, DQB1, DQ promoter polymorphism and extended class I/class II haplotypes in the Seri Indians from Northwest Mexico
Authors: Alaez C. , Infante E. , Pujol J. , Duran C. , Navarro J.L. , Gorodezky C.
Published: March 2003

Abstract:The study of the genetics of the Major Histocompatibility Complex (MHC) in Amerindians is of great value in understanding the origins and migrations of these native groups, as well as the impact of immunogenetics on the epidemiology of diseases affecting these populations. We analyzed, using Polymerase Chain Reaction and Sequence Specific Oligonucleotide Probes (PCR‐SSOP), DRB1, DQA1, DQB1 alleles and the promoter regions of DQA1 and DQB1 genes in 31 unrelated and 24 related Seri, a Mexican Indian group, from the state of Sonora (Northwest Mexico). The class II genotypes of this population were found to be in genetic equilibrium. The allele frequency (AF) of the prevalent DRB1 alleles were DRB1*0407 (48.4%), DRB1*0802 (33.9%) and DRB1*1402 (16.1%). The most frequent DQA1 and DQB1 alleles were DQA1*03011 (AF = 50.00%), DQA1*0401 (AF = 33.87%) and DQA1*0501 (AF = 16.13%); DQB1*0302 (AF = 50.00%), DQB1*0402 (33.87%) and DQB1*0301 (16.13%); which were in combination with DRB1*0407, DRB1*0802 and DRB1*1402, respectively. Three QAP and three QBP alleles were present (QAP 3.1, 4.1, 4.2; QBP 3.1, 3.21, 4.1) associated with the typical published DQA1 and DQB1 alleles. Four class II haplotypes were present in family members: DRB1*0407‐QAP‐3.1‐DQA1*03011‐QBP‐3.21‐DQB1*0302; DRB1*0802‐QAP‐4.2‐DQA1*0401‐QBP‐4.1‐DQB1*0402; DRB1*1402‐QAP‐4.1‐DQA1*0501‐QBP‐3.1‐DQB1*0301 and DRB1*0701‐QAP‐2.1‐DQA1*0201‐QBP‐2.1‐DQB1*0201. The family data were used to confirm extended haplotypes. A total of 21 haplotypes were found when A* and B* loci were also considered. The three most frequent combinations included A*0201‐B*3501‐DRB1*0407, A*3101‐B*5101‐DRB1*0802, and A*0201‐B*40‐DRB1*1402.
HLA‐DRB1 and MHC class 1 chain‐related A haplotypes in Basque families with celiac disease
Authors: Bilbao J.R. , Martín‐Pagola A. , Vitoria J.C. , Zubillaga P. , Ortiz L. , Castaño L.
Published: March 2003

Abstract: The contribution of HLA genes to the genetic risk for celiac disease (CD) has been known for a long time. Recent publications have pointed to the possibility that a second, independent susceptibility locus could be located in the same genomic region, and a triplet repeat polymorphism in exon 5 of the gene MHC class I chain‐related protein A (MICA; located between TNFA and HLA‐B) has been associated with several autoimmune disorders, including type 1 diabetes mellitus (DM1) and Addison's disease. On the other hand, a single amino acid change in exon 3 of MICA (M129V) has been shown to strongly reduce MICA binding to NKG2D, an activating natural killer receptor expressed also on T cells, and this could have significant effects on autoimmune reactions. In this study, we have analyzed the contribution of these polymorphisms to CD in 37 Basque families, and have constructed MICA‐HLA‐DRB1 haplotypes to determine whether MICA has an effect independent from the HLA class II conferred risk. In our population, HLA‐DRB1*0301 was associated with an increased risk for CD, while HLA‐DRB1*1501 conferred protection from the disease (OR: 7.38 and 0.06, respectively). On the other hand, MICA allele A4 was positively associated with the disease (OR: 4.69) whereas allele A9 showed a trend towards protection (OR: 0.18), although significance did not hold after correction. No association of the exon 3 biallelic polymorphism was observed. A positive allelic association was found for haplotypes A5.1‐DRB1*0301 (associated with risk for disease), A4‐DRB1*0301 and A6‐DRB1*07. In view of our results, both HLA‐DRB1 and MICA are associated with CD, but stratification analysis did not show any independent contribution of the MICA polymorphisms analyzed to CD risk. Besides, MICA allele A4 (also A5.1 was associated with risk for CD and other diseases) is in strong linkage disequilibrium with HLA‐DRB1*0301. Finally, the major histocompatibility complex region's conferred susceptibility to CD, at least in Basque, is very similar to that observed for DM1, with shared risk and protective haplotypes.
Population genetic relationships between Mediterranean populations determined by HLA allele distribution and a historic perspective
Authors: Arnaiz‐Villena A. , Gomez‐Casado E. , Martinez‐Laso J.
Published: March 2003

Abstract: HLA genes allele distribution has been studied in Mediterranean and sub‐Saharan populations. Their relatedness has been tested by genetic distances, neighbour‐joining dendrograms and correspondence analyses. The population genetic relationships have been compared with the history of the classical populations living in the area. A revision of the historic postulates would have to be undertaken, particularly in the cases when genetics and history are overtly discordant. HLA genomics shows that: 1) Greeks share an important part of their genetic pool with sub‐Saharan Africans (Ethiopians and west Africans) also supported by Chr 7 Markers. The gene flow from Black Africa to Greece may have occurred in Pharaonic times or when Saharan people emigrated after the present hyperarid conditions were established (5000 years B.C.). 2) Turks (Anatolians) do not significantly differ from other Mediterraneans, indicating that while the Asians Turks carried out an invasion with cultural significance (language), it is not genetically detectable. 3) Kurds and Armenians are genetically very close to Turks and other Middle East populations. 4) There is no HLA genetic trace of the so called Aryan invasion, which has only been defined on doubtful linguistic bases. 5) Iberians, including Basques, are related to north‐African Berbers. 6) Present‐day Algerian and Moroccan urban and country people show an indistinguishable Berber HLA profile.
HLA polymorphism in Bulgarians defined by high‐resolution typing methods in comparison with other populations
Authors: Ivanova M. , Rozemuller E. , Tyufekchiev N. , Michailova A. , Tilanus M. , Naumova E.
Published: March 2003

Abstract: In the present study we analyzed for the first time HLA class I and class II polymorphisms defined by high‐resolution typing methods in the Bulgarian population. Comparisons with other populations of common historical background were performed. Most HLA‐A, ‐B, ‐DRB alleles and haplotypes observed in the Bulgarian population are also common in Europe. Alleles and haplotypes considered as Mediterranean are relatively frequent in the Bulgarian population. Observation of Oriental alleles confirms the contribution of Asians to the genetic diversity of Bulgarians. The use of high‐resolution typing methods allowed to identify allele variants rare for Europeans that were correlated to specific population groups. Phylogenetic and correspondence analyses showed that Bulgarians are more closely related to Macedonians, Greeks, and Romanians than to other European populations and Middle Eastern people living near the Mediterranean. The HLA‐A,‐B,‐DRB1 allele and haplotype diversity defined by high‐resolution DNA methods confirm that the Bulgarian population is characterized by features of southern European anthropological type with some influence of additional ethnic groups. Implementation of high‐resolution typing methods allows a significantly wider spectrum of HLA variation to be detected, including rare alleles and haplotypes, and further clarifies the origin of Bulgarians.
TNFA–TNFB haplotypes modify susceptibility to type I diabetes mellitus independently of HLA class II in a Moroccan population
Authors: Bouqbis L. , Akhayat O. , Garchon H.‐J. , Calafell F. , Izaabel H.
Published: March 2003

Abstract: The contribution of single nucleotide polymorphisms in tumor necrosis factors (TNF) α and β to autoimmune diseases, and to type 1 diabetes mellitus (T1DM) in particular, is not well established, and may be confounded by linkage disequilibrium to class II HLA genes. At least two polymorphisms seem to have functional relevance in the respective genes: TNFA‐307 and TNFB+252. We have typed these two polymporphisms in samples of Moroccan T1DM patients and controls for which class II HLA genes had already been typed. Tumor necrosis factors and compound TNF‐class II HLA haplotypes were inferred; it was the first time that such a design had been implemented. Independent of linkage disequilibrium with class II HLA, TNF haplotype TNFA‐307*2 – TNFB+252*2 showed a significant protective effect (OR = 0.031), partly exacerbated by partial linkage to protective class II haplotypes. Such effect could be detected because Morocco shows the highest frequency of the TNFA‐307*2 allele yet reported. This highlights the possible population differences in alleles contributing to autoimmune diseases.
The conformational and biological analysis of a cyclic anti‐obesity peptide from the C‐terminal domain of human growth hormone
Authors: Ogru E. , Heffernan M. , Jiang W.‐J. , Libinaki R. , Ng F. , Wilson J.C. , Chalmers D.K.
Published: March 2003

Abstract: The three‐dimensional solution structure of anti‐obesity drug (AOD), a 15‐residue, disulfide‐bonded, cyclic peptide, cyclo(6,13)‐H2N‐Leu‐Arg‐Ile‐Val‐Gln‐Cys‐Arg‐Ser‐Val‐Glu‐Gly‐Ser‐Cys‐Gly‐Phe‐OH, derived from the C‐terminal domain of the human growth hormone (hGH) (residues 177–191) was determined using two‐dimensional 1H NMR spectroscopy. AOD stimulates lipolysis and inhibits lipogenesis, in vitro, in rodent, porcine and human adipose tissues. These biological effects suggest that AOD is a potential therapeutic candidate for the treatment of obesity. Conformational studies of AOD were conducted in aqueous solution and in water/dimethylsulfoxide mixtures. In general, spectral quality was superior in the water/dimethylsulfoxide mixtures. The cyclic region of AOD in water/dimethylsulfoxide adopts type I β‐turns at residues Ser8‐Val9‐Glu10‐Gly11 and Ser12‐Cys13‐Gly14‐Phe15, each preceded by loop‐like structures. Comparison of the conformation of this peptide with residues 177–191 in the native hGH protein X‐ray crystal structure indicates that the synthetic peptide retains some structural similarity to the intact protein. This study provides evidence that the C‐terminal region of hGH is a specific functional domain of the multifunctional hGH protein.
Synthesis of cyclopentapeptides and cycloheptapeptides by DEPBT and the influence of some factors on cyclization
Authors: Tang Yan‐chun , Xie Hai‐bo , Tian Gui‐ling , Ye Yun‐hua
Published: March 2003

Abstract: Three cyclic peptides – cyclo(GlyAlaTyrLeuAla), cyclo(GlyProTyrLeuAla) and cyclo(GlyTyrGlyGlyProPhePro) – isolated and identified from medicinal herbs were chosen as model cyclic peptides to study the influence of the linear precursors and coupling reagents on cyclization. The 17 linear precursors of these three cyclic peptides were synthesized and cyclized using 3‐(diethoxyphosphoryloxy)‐(1–3)‐benzotriazin‐4 (3H)‐one (DEPBT) as the major coupling reagent. The present work shows that: (i) the effects of linear peptide precursors on the cyclization are complex but some guidelines for choosing suitable precursor for cyclization could be considered; and (ii) DEPBT results in a higher cyclization yield compared with other coupling reagents. In addition, it was confirmed that peptides containing alternating d and l residues favor cyclization.
Hemoxidation and binding of the 46‐kDa cystalysin of Treponema denticola leads to a cysteine‐dependent hemolysis of human erythrocytes
Authors: Chu L. , Ebersole J. L. , Holt S. C.
Published: March 2003

Cystalysin, a 46‐kDa protein isolated from the cytosol of Treponema denticola, was capable of both cysteine dependent hemoxidation and hemolysis of human and sheep red blood cells. The activities were characteristic of a cysteine desulfhydrase. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS‐PAGE) and Western immunoblotting analysis of the interaction of cystalysin with the red blood cells revealed an interaction of the protein with the red blood cell membrane. Substrates for the enzyme (including
l‐cysteine and β‐chloroalanine) enhanced the interaction, which occurred with both whole red blood cells as well as with isolated and purified red blood cell ghosts. SDS‐PAGE and western immunoblotting employing anti‐hemoglobin serum revealed that, during the hemoxidative events, the hemoglobin molecule associated with the red blood cell membrane, forming putative Heinz bodies. Spectrophotometric analysis of the hemoxidative events (cystalysin+cysteine+red blood cells) revealed a chemical modification of the native hemoglobin to sulfhemoglobin and methemoglobin. Hemoxidation also resulted in the degradation of both the red blood cell α‐ and β‐spectrin. The results presented suggest that the interaction of cystalysin with the red blood cell membrane results in the chemical oxidation of the hemoglobin molecule as well as an alteration in the red blood cell membrane itself.
Gingival crevicular fluid inflammatory mediators and bacteriology of gingivitis in nonhuman primates related to susceptibility to periodontitis
Authors: Ebersole J. L. , Cappelli D. , Holt S. C. , Singer R. E. , Filloon T.
Published: March 2003

The hypothesis to be tested was that the microbiota and resulting local host inflammatory response characteristics in oral conditions of high levels of chronic gingival inflammation increases susceptibility to progressing periodontitis. This study used cynomolgus monkeys, Macaca fascicularis (nonhuman primates), with high and low levels of long‐standing gingival inflammation to define the profiles of gingival crevicular fluid mediators, cytokines and immunoglobulins; describe the subgingival microbiota; and evaluate their susceptibility to ligature‐induced periodontitis. Sixteen nonhuman primates were stratified into two groups (HI, LO) based upon Bleeding Index as a measure of the natural level of inflammation (HI=1.26±0.45; LO=0.22±0.16). The host mediator levels, subgingival microbiota, and clinical characteristics of the LO and HI groups were compared after 30 days of oral hygiene, during a 30 day experimental gingivitis (7, 14, and 30 days), and during periodontitis (30, 60, and 90 days). The results demonstrated that nonhuman primates with high levels of long‐standing gingival inflammation when compared to those nonhuman primates with low inflammation show: 1) different inflammatory mediator profiles in gingival crevicular fluid (particularly for immunoglobulin A (IgA) and IgG levels), 2) a different quantitative and qualitative subgingival microbiota; and 3) a similar progression of periodontitis. Thus, while variations in host inflammatory responses to local factors exist in the nonhuman primates, an extensive subgingival challenge (such as ligation) may negate these individual differences.
Cytokine profiles in parotid saliva from HIV‐1‐infected individuals: changes associated with opportunistic infections in the oral cavity
Authors: Black K. P. , Merrill K. W. , Jackson S. , Katz J.
Published: March 2003

The purpose of this study was to quantitate levels of cytokines in parotid saliva of subjects infected with human immunodeficiency virus‐1 (HIV‐1) and to determine if the cytokine profiles differ in subjects with an oral opportunistic infection, i.e., candidiasis or oral hairy leukoplakia. Parotid saliva samples were obtained from HIV‐infected individuals with or without candidiasis or oral hairy leukoplakia and from healthy controls and were assessed by ELISA for levels of interleukin (IL)‐1, IL‐2, IL‐4, IL‐5, IL‐10, transforming growth factor‐β, tumor necrosis factor‐α and interferon (IFN)‐γ. Saliva from HIV‐infected subjects with oral candidiasis had significantly higher levels of IFN‐γ than that seen in HIV‐infected individuals with no oral disease and significantly higher levels of IL‐2, IL‐5 and IFN‐γ than saliva of healthy controls. No significant difference was seen in cytokine levels in saliva from HIV‐infected subjects with no oral infections and healthy controls. The HIV‐infected subjects with oral hairy leukoplakia displayed significantly higher levels of both IL‐1α and IFN‐γ compared with the HIV and no oral disease group and a higher level of IFN‐γ than seen in saliva from the healthy control group. In comparing cytokine levels from both HIV and oral disease groups, significant differences were detected in levels of IL‐5 and IL‐10. These results indicate that the profile of salivary cytokines is altered as a result of the oral opportunistic infection candidiasis or oral hairy leukoplakia and also by concurrent HIV infection.
Comparison of virulence factors of oral Candida dubliniensis and Candida albicans isolates in healthy people and patients with chronic candidosis
Authors: Hannula J. , Saarela M. , Dogan B. , Paatsama J. , Koukila‐Kähkölä P. , Pirinen S. , Alakomi H.‐L. , Perheentupa J. , Asikainen S.
Published: March 2003

We determined differences in the expression of certain virulence factors between oral Candida dubliniensis and Candida albicans species. In addition, clonal differences were sought among C. albicans isolates recovered from patients with and without compromised immune system. The material comprised 93 clinical yeast isolates originated in 40 subjects (1–5 isolates per subject). All 26 C. dubliniensis isolates and 46 C. albicans isolates originated from healthy routine dental clinic patients. Additionally, 21 C. albicans isolates were collected from patients with autoimmune polyendocrinopathy–candidosis–ectodermal dystrophy (APECED), who have chronic candidosis as one manifestation of their immunocompromising disease. Polymerase chain reaction amplification using the random sequence primer OPE‐03 enabled grouping of the C. dubliniensis isolates in 2 genotypes (I and II) and C. albicans isolates in 15 genotypes (I–XV). No significant difference was found in the distribution of genotypes between the patients with APECED and the healthy subjects. C. dubliniensis isolates exhibited high‐frequency phenotypic switching significantly more frequently than did C. albicans isolates, and vice versa regarding phospholipase and proteinase production. Proteinase production was significantly more frequent among C. albicans genotype V than genotype IX isolates. No significant difference was found in expression of virulence factors of C. albicans isolates between the patients with APECED and the healthy subjects.
Herpesviruses: a unifying causative factor in periodontitis?
Authors: Slots J. , Contreras A.
Published: March 2003

Human cytomegalovirus and Epstein‐Barr virus type 1 are discussed in this review as they relate to destructive periodontal disease in humans. Genomes of the two herpesviruses occur frequently in severe adult periodontitis, localized and generalized juvenile periodontitis, Papillon‐Lefèvre syndrome periodontitis, Down’s syndrome periodontitis, HIV‐associated periodontitis and acute necrotizing ulcerative gingivitis. Herpesvirus infections generally involve a mild or asymptomatic primary phase followed by an asymptomatic latent phase interrupted sporadically by periods of activation, where viral replication and possibly clinical disease become manifest. Herpesvirus reactivation is triggered by a number of immunosuppressing factors, some of which have also been shown to be risk indicators of periodontal disease. Available evidence argues for the involvement of active cytomegalovirus infection in the initiation and progression of localized juvenile periodontitis and possibly other types of periodontal disease. In periodontal disease, herpesviruses may cause release of tissue‐destructive cytokines, overgrowth of pathogenic periodontal bacteria, and initiation of cytotoxic or immunopathogenic events. Understanding the significance of herpesviruses in the causation and pathogenesis of destructive periodontal diseases may have important implications in future prevention and treatment of the diseases.
Rate‐limiting steps of glucose and sorbitol metabolism in Streptococcus mutans cells exposed to air
Authors: Iwami Y. , Takahashi‐Abbe S. , Takahashi N. , Abbe K. , Yamada T.
Published: March 2003

It has been supposed that rate of sorbitol metabolism in the air‐exposed streptococcal cells could be limited by the low capacity to regenerate nicotinamide adenine dinucleotide (NAD) from reduced NAD (NADH) following inactivation of pyruvate formate‐lyase by oxygen. The rate‐limiting steps, however, have not been identified. The aim of this study was to examine the effect of temporary exposure of the streptococcal cells to air on the intracellular flux of glucose and sorbitol metabolism by measuring acid excretion, fluorescence dependent on cellular level of NADH, glycolytic intermediates and enzyme activities. The exposure of cells to air decreased the acid excretions during glucose and sorbitol metabolism. The analysis of the glycolytic intermediates and the fluorescence suggested that the reduced level of acid excretion in the air‐exposed glucose metabolizing cells resulted from the decrease in pyruvate catabolism. In the presence of sorbitol, the decreased acid production resulted from the reduced rates of the reactions catalyzed by sorbitol‐phosphoenolpyruvate phosphotransferase and sorbitol 6‐phosphate dehydrogenase because of shortage of substrates for these enzymes in addition to the decrease in pyruvate catabolism.
Characterization of the cathepsin B–like proteinases of Trichomonas tenax ATCC 30207
Authors: Yamamoto A. , Asaga E. , Nagao E. , Igarashi T. , Goto N.
Published: March 2003

An oral parasite Trichomonas tenax ATCC 30207 synthesizes and secretes various proteinases. By gelatin‐SDS‐PAGE, we found five proteinases bands (30, 37, 46, 51 and 60 kDa) in cell lysate and four bands (37, 45, 52 and 60 kDa) in culture filtrate. The proteinases hydrolyzed acid soluble type I collagen as well as gelatin. The enzymes were suggested to possess typical characteristics of cysteine proteinases based on the patterns of inhibition and activation by various factors. Based on relative efficiencies of synthetic substrates, most of them were most likely cathepsin B–like enzymes.
Morphological analysis of Helicobacter pylori from gastric biopsies and dental plaque by scanning electron microscopy
Authors: Young K. A. , Allaker R. P. , Hardie J. M.
Published: March 2003

Helicobacter pylori is rarely cultured from sites other than the gastric mucosa. The morphology of H. pylori in the stomach and dental plaque of adult dyspeptic patients was investigated to determine whether a difference in morphology at these sites could explain the inability to culture the organism from the oral cavity. Five adult patients attending for an upper gastrointestinal endoscopy were investigated. Dental plaque and gastric antral biopsy samples were analysed by culture and polymerase chain reaction (PCR) both before and after immunomagnetic separation using polyclonal rabbit anti–H. pylori IgG. Bead:bacteria aggregates were then examined by scanning electron microscopy (SEM). Rod and coccoid forms of H. pylori were seen by SEM in all oral and gastric samples which were H. pylori PCR positive. Although rod and coccoid forms have previously been shown to be associated with the gastric mucosa, this is the first time H. pylori cells have been visualized in dental plaque.
Salivary anticandidal activity and saliva composition in an HIV‐infected cohort
Authors: Lin A. L. , Johnson D. A. , Patterson T. F. , Wu Y. , Lu D. L. , Shi Q. , Yeh C.‐K.
Published: March 2003

This study investigated salivary anticandidal activity and salivary composition in stimulated whole saliva of 18 advanced HIV‐infected patients and compared these values to healthy controls. Stimulated whole saliva from HIV‐infected patients showed decreased anticandidal activity. The flow rate was reduced by 40% as compared with controls. The saliva flow rate for HIV‐infected patients who had recoverable yeast in their saliva was reduced as compared to HIV‐infected patients without recoverable yeast. For HIV‐infected patients, the saliva concentrations of lactoferrin, secretory IgA and Cl− were increased while the secretion rate of lysozyme, total protein and K+ were reduced. There was no difference in any parameter as a function of taking the antifungal drug fluconazole. There was no association between salivary anticandidal activity and any salivary component. This study shows reduced anticandidal activity and salivary flow rate in HIV‐infected patients. These alterations may contribute to their increased incidence of oral candidal infections.