bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental condensation inhibition in constitutive and facultative heterochromatin of mammalian chromosomes
Authors: Haaf T. , Schmid M.
Published: April 2003

What drives the dramatic changes in chromosome structure during the cell cycle is one of the oldest questions in genetics. During mitosis, all chromosomes become highly condensed and, as the cell completes mitosis, most of the chromatin decondenses again. Only chromosome regions containing constitutive or facultative heterochromatin remain in a more condensed state throughout interphase. One approach to understanding chromosome condensation is to experimentally induce condensation defects. 5-Azacytidine (5-aza-C) and 5-azadeoxycytidine (5-aza-dC) drastically inhibit condensation in mammalian constitutive heterochromatin, in particular in human chromosomes 1, 9, 15, 16, and Y, as well as in facultative heterochromatin (inactive X chromosome), when incorporated into late-replicating DNA during the last hours of cell culture. The decondensing effects of 5-aza-C analogs, which do not interfere with normal base pairing in substituted duplex DNA, have been correlated with global DNA hypomethylation. In contrast, decondensation of constitutive heterochromatin by incorporation of 5-iododeoxyuridine (IdU) or other non-demethylating base analogs, or binding of AT-specific DNA ligands, such as berenil and Hoechst 33258, may reflect an altered steric configuration of substituted or minor-groove-bound duplex DNA. Consequently, these compounds exert relatively specific effects on certain subsets of AT-rich constitutive heterochromatin, i.e. IdU on human chromosome 9, berenil on human Y, and Hoechst 33258 on mouse chromosomes, which provide high local concentrations of IdU incorporation sites or DNA-ligand-binding sites. None of these non-demethylating compounds affect the inactive X chromosome condensation. Structural features of chromosomes are largely determined by chromosome-associated proteins. In this light, we propose that both DNA hypomethylation and steric alterations in chromosomal DNA may interfere with the binding of specific proteins or multi-protein complexes that are required for chromosome condensation. The association between chromosome condensation defects, genomic instability, and epigenetic reprogramming is discussed. Chromosome condensation may represent a key ancestral mechanism for modulating chromatin structure that has since been realloted to other nuclear processes.
Chromosomes of the antelope genus Kobus (Artiodactyla, Bovidae): karyotypic divergence by centric fusion rearrangements
Authors: Kingswood S.C. , Kumamoto A.T. , Charter S.J. , Houck M.L. , Benirschke andK.
Published: April 2003

G- and C-banded karyotypes of four species of the genus Kobus were compared using the standard karyotype of Bos taurus. Chromosomal complements were 2n = 50–54 in K. ellipsiprymnus, 2n = 50 in K. kob, 2n = 48 in K. leche, and 2n = 52 in K. megaceros. The number of autosomal arms in all karyotypes was 58. Fifteen autosomal pairs were conserved among these four species, including the 1;19 and 2;25 centric fusions, and autosomal differences involved eight centric fusion rearrangements. Five centric fusions were each unique to a particular taxon: 3;10 (K. leche), 3;11 and 6;29 (K. kob), and 5;17 and 7;11 (K. ellipsiprymnus). The 4;7 fusion occurred in K. leche and K. megaceros, whereas the 5;13 fusion occurred in K. kob and K. leche; the 6;18 fusion was found in three species but was absent in K. kob. Differences between the X chromosomes of the four Kobus species were attributed to heterochromatic additions or deletions, and Y-chromosome differences may have been the result of pericentric inversion. G-banded karyotypes of putative K. l. leche and K. l. kafuensis appeared identical, as did C-banded karyotypes of the two subspecies. Karyotypes of K. e. ellipsiprymnus and K. e. defassa differed as a result of the 6;18 centric fusion, which was polymorphic in K. e. defassa, and the 7;11 centric fusion, which was polymorphic in K. e. ellipsiprymnus but absent in K. e. defassa. Several centric fusions were related by monobrachial chain-IV complexes; however, records of hybridization indicate that reproductive isolation between at least certain species of Kobus is incomplete. Karyotypic differences between K. ellipsiprymnus (including K. e. ellipsiprymnus and K. e. defassa), K. kob, K. leche, and K. megaceros support the validity of these taxa, as well as the need to manage them as separate populations.
Expression of a candidate gene for the gonadoblastoma locus in gonadoblastoma and testicular seminoma
Authors: Lau Y.-F.C. , Chou P.M. , Iezzoni J.C. , Alonzo J.A. , Kömüves L.G.
Published: April 2003

The gonadoblastoma locus on the Y chromosome (GBY) predisposes the dysgenetic gonads of XY females to develop in situ tumors. It has been mapped to a critical interval on the short arm and adjacent centromeric region on the Y chromosome. Currently there are five functional genes identified on the GBY critical region, thereby providing likely candidates for this cancer predisposition locus. To evaluate the candidacy of one of these five genes, testis-specific protein Y-encoded (TSPY), as the gene for GBY, expression patterns of TSPY in four gonadoblastoma from three patients were analyzed by immunohistochemistry using a TSPY specific antibody. Results from this study showed that TSPY was preferentially expressed in tumor germ cells of all gonadoblastoma specimens. Additional study on two cases of testicular seminoma demonstrated that TSPY was also abundantly expressed in all stages of these germ cell tumors. The present observations suggest that TSPY may either be involved in the oncogenesis of or be a useful marker for both types of germ cell tumors.
BLM, the Bloom’s syndrome protein, varies during the cell cycle in its amount, distribution, and co-localization with other nuclear proteins
Authors: Sanz M.M. , Proytcheva M. , Ellis N.A. , Holloman W.K. , German J.
Published: April 2003

BLM, the protein encoded by the gene mutated in Bloom’s syndrome (BS), is a phylogenetically highly conserved DNA helicase that varies in amount and distribution in the nucleus during the cell-division cycle. It is undetectable in many cells as they emerge from mitosis but becomes abundant during G1 and remains so throughout S, G2, and mitosis. BLM is widely distributed throughout the nucleus but at certain times also becomes concentrated in foci that vary in number and size. It co-localizes transitorily with replication protein A (RPA) and promyelocytic leukemia protein (PML) nuclear bodies, and at times it enters the nucleolus. The observations support the hypothesis that BLM is distributed variously about the nucleus to manipulate DNA in some, very possibly several, nucleic acid transactions, when and where they take place. The specific transaction(s) remain to be identified. Although absence from the nucleus of functional BLM – the situation in BS – obviously is not lethal in the human, other helicases would appear to be unable to substitute for it completely, witness the hypermutability and hyperrecombinability of BS cells.
Differences in the meiotic pairing behavior of gonosomal heterochromatin between female and male Microtus agrestis: implications for the mechanism of heterochromatin amplification on the X and Y
Authors: Singh A.P. , Henschel S. , Sperling K. , Kalscheuer V. , Neitzel H.
Published: April 2003

It is generally thought that pairing and recombination between the X and Y chromosome in eutherian mammals is important for the occurrence of normal meiotic division and the production of functional gametes. Microtus agrestis is one of the examples whose giant and heterochromatin-rich sex chromosomes fail to establish a durable association at any stage of the first meiotic division in males. In contrast, in females, synapsis starts in the euchromatic short arm and pairing progresses unidirectionally and continues until both X chromosomes have paired completely, as can be demonstrated by the use of fluorescence in situ hybridization with a sequence confined to the non-centromeric, gonosomal heterochromatin. However, compared with euchromatin, this association is apparently ephemeral and breaks off precociously in the pachytene and metaphase I stages. We demonstrate that a middle repetitive element is localized interspersed in the noncentromeric heterochromatin of both X and Y, except the telomeric region of the Y. No differences could be detected at the molecular level between male and female DNA, indicating that at least the bulk of these elements are organized in the same manner on the X and Y. Our data imply that the loss of synapsis and recombination between the X and Y might have preceded the process of heterochromatin amplification in the course of Microtinae evolution. Since asynapsed elements are particularly susceptible to DNA strand breaks during prophase I, DNA repair of double-strand breaks involving heterochromatic segments of the X and Y could have resulted in translocations of larger segments from the X to the Y or vice versa during the course of chromosome evolution of the gonosomes, explaining the homology at the molecular level between the heterochromatin of the asynaptic X and Y in M. agrestis.
Some problems in the genetics of X-linked mental retardation
Authors: Tariverdian G. , Vogel F.
Published: April 2003

X-linked mental retardation has recently become one of the most interesting genetic anomalies. Studying this group of conditions has led to many insights into the mechanisms involved in normal and abnormal gene actions in humans. Since the early 1980s, the number of disease entities for which the responsible genes could be localized on the X chromosome has increased from year to year; at the Ninth International Workshop on Fragile-X-Syndrome and X-linked Mental Retardation, 199 such disease units were counted (Hamel, 1999). Conventionally, these units were subdivided into two groups: syndromal and non-syndromal types. The syndro- mal types are characterized by external features, neurological signs, and/or metabolic anomalies. The non-syndromal types do not show such specific features; here, the X-linked mode of inheritance is the only indicator. Due to the reduced reproduction of mentally severely retarded males, a relatively high fraction of new mutants among cases of a specific type must be expected. It cannot be the purpose of the present short article to review sufficiently well the entire field; this would require a complete book. Rather, it is our intention to point to some open problems and possible ways for their solution.
The minimal mammalian Y chromosome – the marsupial Y as a model system
Authors: Toder R. , Wakefield M.J. , Graves J.A.M.
Published: April 2003

The mammalian X and Y chromosomes are very different in size and gene content. The Y chromosome is much smaller than the X and consists largely of highly repeated non-coding DNA, containing few active genes. The 65-Mb human Y is homologous to the X over two small pseudoautosomal regions which together contain 13 active genes. The heterochromatic distal half of the human Yq is entirely composed of highly repeated non-coding DNA, and even the euchromatic portion of the differential region is largely composed of non-coding repeated sequences, amongst which about 30 active genes are located. The basic marsupial Y chromosome (about 10 Mb) is much smaller than that of humans or other eutherian mammals. It appears to include no PAR, since it does not undergo homologous pairing, synaptonemal complex formation or recombination with the X. We show here that the tiny dunnart Y chromosome does not share cytogenetically detectable sequences with any other chromosome, suggesting that it contains many fewer repetitive DNA sequences than the human or mouse Y chromosomes. However, it shares several genes with the human and/or mouse Y chromosome, including the sex determining gene SRY and the candidate spermatogenesis gene RBMY, implying that the marsupial and eutherian Y are monophyletic. This minimal mammalian Y chromosome might provide a good model Y in which to hunt for new mammalian Y specific genes.
A high-density transcript map of the human dominant optic atrophy OPA1 gene locus and re-evaluation of evidence for a founder haplotype
Authors: Murton N.J. , French L. , Toomes C. , Joseph S.S. , Rehman I. , Hopkins B.L. , Inglehearn C.F. , Churchill A.J.
Published: April 2003

Dominant optic atrophy (DOA, gene OPA1) is the commonest form of inherited optic atrophy. Linkage studies have shown that a locus for this disease lies in a 1.4-cM region at chromosome 3q28→q29 and have suggested a founder haplotype for as many as 95% of the linked families. To aid the identification of candidate genes for this disease, we have constructed a Bacterial Artificial Chromosome (BAC) contig covering approximately 3.3 Mb and encompassing the OPA1 critical region (flanking markers D3S3669 and D3S3562). This physical map corrects errors in the marker order reported in the literature, allowing the OPA1 critical region to be precisely defined. A reassessment of the founder effect in the light of the revised marker order suggests that it may not be as significant as had previously been suggested. A high-density transcript map was created by precisely mapping genes and expressed sequence tags (ESTs) from GeneMap’99, that have been loosely assigned to the region by radiation hybrid mapping. One known gene (KIAA0567 protein) and 15 ESTs were found to lie within the minimal disease region. Analysis of the sequence data already available from within the OPA1 critical region allowed the identification and mapping of a further 31 ESTs. The work presented in this study provides the basis for the characterisation of candidate genes and the ultimate identification of the gene mutated in DOA.
Human puromycin-sensitive aminopeptidase: cloning of 3′ UTR, evidence for a polymorphism at aa 140 and refined chromosomal localization to 17q21
Authors: Bauer W.O. , Nanda I. , Beck G. , Schmid M. , Jakob F.
Published: April 2003

Puromycin-sensitive aminopeptidase is a predominantly cytoplasmatic zinc-dependent exopeptidase. Its physiological function is not known to date. Here we report data on tissue distribution, a polymorphism within the coding region and the complete 3′ UTR. The gene (NPEPPS alias PSA) was physically mapped to chromosome 17q21.2→q21.32 using fluorescence in situ hybridization.
Cloning and molecular characterization of three Ubiquitin Fusion Degradation 1 (Ufd1) ortholog genes from Xenopus laevis, Gallus gallus andDrosophila melanogaster
Authors: Ratti A. , Amati F. , Bozzali M. , Conti E. , Sangiuolo F. , Berloco M. , Palumbo G. , Botta A. , Pizzuti A. , Novelli G. , Dallapiccola B.
Published: April 2003

The yeast ubiquitin fusion degradation 1 (Ufd1) protein is involved in a degradation pathway for ubiquitin fused products. The human ortholog gene (UFD1-like, UFD1L) is deleted in patients affected by the DiGeorge/velocardiofacial syndromes. We report the cloning of UFD1L orthologs from Drosophilamelanogaster (dufd1l), Xenopus laevis and Gallus gallus. The 1,125-bp Drosophila cDNA encodes a protein of 316 amino acids, showing 60% identity with the human and murine proteins. The identity to the G. gallus, X. laevis, C. elegans and S. cerevisiae proteins is 95%, 83%, 32%, and 36%, respectively. Northern expression data in Drosophila indicate that dufd1l is expressed through embryonic, larval and pupal development, as well as in the adult fly.
Genomic structure, chromosome mapping and expression analysis of the human AXIN2 gene
Authors: Dong X. , Seelan R.S. , Qian C. , Mai M. , Liu W.
Published: April 2003

Conductin is a Wnt signalling protein and serves as a negative regulator of β-catenin stability. We have previously isolated the human homolog (AXIN2) of the murine conductin gene and shown that it is mutated in colorectal cancer (CRC) with defective mismatch repair (MMR). Here we report the detailed genomic structure of this gene by analysis of cDNA and genomic clones. The gene spans ≧25 kb containing ten exons ranging from 96 bp to 904 bp. All splice donor and acceptor sites conform to the GT/AG rule. FISH (Fluorescence in situ Hybridization) analysis localized this gene to human chromosome band 17q24 and showed that it exists as a single copy in the human genome. Northern blot analysis from different human organs demonstrated that the AXIN2 gene is highly expressed in human thymus, prostate, testis, small intestine and ovarian tissues but expressed at a lower level in colon. The data reported here provides a framework for further analysis of this important Wnt signalling protein in vertebrate development and tumorigenesis.
DNA amplification associated with double minutes originating from chromosome 19 in mouse hepatocellular carcinoma
Authors: Zimonjic D.B. , Zhang H. , Shan Z. , Factor V. , Trent J. , Thorgeirsson S.S. , Popescu N.C.
Published: April 2003

DNA amplification is associated with genomic instability, the main characteristic of cancer cells, and it frequently involves protooncogenes. Double minute chromosomes (DM) and homogeneously stained regions (HSR) are cytological manifestations of DNA amplification. Gain of chromosome 19 is a recurrent alteration in mouse hepatocellular carcinoma (HCC). In one tumor cell line established from HCC developed in myc transgenic mice, DM derived from chromosome 19 were identified by spectral karyotyping and confirmed by fluorescence in situ hybridization (FISH). A probe generated by PCR from microdissected DM was localized by FISH on normal and HCC-derived cell lines on DM and chromosome 19 at two sites separated by several medium size G-bands. This organization of DM containing amplified sequences from separate loci of the same chromosome, indicates a complex mechanism of DNA amplification, possibly involving more than one gene. DM or HSR were not previously identified in mouse HCC and adult human HCC. The recognition of these loci could lead to the cloning of new genes or identification of known genes important in development or progression of HCC.
Comparative genomic hybridization based strategy for the analysis of different chromosome imbalances detected in conventional cytogenetic diagnostics
Authors: Tönnies H. , Stumm M. , Wegner R.-D. , Chudoba I. , Kalscheuer V. , Neitzel H.
Published: April 2003

Today, conventional cytogenetics (CC) is the main technique in routine genetic diagnostics for the analysis of genotype/phenotype correlations. Additionally, fluorescence in situ hybridization (FISH) has proven to be useful for the characterization of structural chromosome aberrations found in conventional cytogenetics. Comparative genomic hybridization (CGH) is a molecular cytogenetic FISH approach developed for the detection of genomic imbalances with cytogenetic resolution. CGH allows the genome-wide assessment of relative DNA copy number changes using extracted specimen DNA as a probe. We investigated the capacity of CGH in cases referred for conventional cytogenetic diagnostics for the detection of chromosome imbalances. Three different groups of conspicuous karyotypes after CC (intrachromosomal rearrangements, interchromosomal rearrangements, and additional marker chromosomes) in pre- and postnatal diagnostic cases were surveyed by CGH to characterize the underlying imbalances of chromosome segments. All together, we investigated more than 100 cases by CGH and validated the results with other molecular cytogenetic methods. Here we present eight of these cases in order to demonstrate our CGH based strategy to analyze chromosomal de novo rearrangements. CGH provided additional cytogenetic information to complement conventional cytogenetic investigations. Additionally, CGH refined the description of the aberrant chromosome segments allowing us to further characterize the underlying mechanisms involved.
Comparative architectural aspects of regions of conserved synteny on human chromosome 11p15.3 and mouse chromosome 7 (including genes WEE1 and LMO1)
Authors: Cichutek A. , Brueckmann T. , Seipel B. , Hauser H. , Schlaubitz S. , Prawitt D. , Hankeln T. , Schmidt E.R. , Winterpacht A. , Zabel B.U.
Published: April 2003

Human chromosome 11p15.3 is associated with chromosome aberrations in the Beckwith Wiedemann Syndrome and implicated in the pathogenesis of different tumor types including lung cancer and leukemias. To date, only single tumor-relevant genes with linkage to this region (e.g. LMO1) have been found suggesting that this region may harbor additional potential disease associated genes. Although this genomic area has been studied for years, the exact order of genes/chromosome markers between D11S572 and the WEE1 gene locus remained unclear. Using the FISH technique and PAC clones of the flanking markers we determined the order of the genomic markers. Based on these clones we established a PAC contig of the respective region. To analyse the chromosome area in detail the synteny of the orthologous region on distal mouse chromosome 7 was determined and a corresponding mouse clone contig established, proving the conserved order of the genes and markers in both species: “cen–WEE1–D11S2043–ZNF143–RANBP7–CEGF1– ST5–D11S932–LMO1–D11S572–TUB–tel”, with inverted order of the murine genes with respect to the telomere/centromere orientation. The region covered by these contigs comprises roughly 1.6 MB in human as well as in mouse. The genomic sequence of the two subregions (around WEE1 and LMO1) in both species was determined using a shotgun sequencing strategy. Comparative sequence analysis techniques demonstrate that the content of repetitive elements seems to decline from centromere to telomere (52.6% to 34.5%) in human and in the corresponding murine region from telomere to centromere (41.87% to 27.82%). Genomic organisation of the regions around WEE1 and LMO1 was conserved, although the length of gene regions varied between the species in an unpredictable ratio. CpG islands were found conserved in putative promoter regions of the known genes but also in regions which so far have not been described as harboring expressed sequences.
Integration of porcine chromosome 13 maps
Authors: van Poucke M. , Yerle M. , Tuggle C. , Piumi F. , Genêt C. , van Zeveren A. , Peelman L.J.
Published: April 2003

In order to expand the comparative map between human chromosome 3 (HSA3) and porcine chromosome 13 (SSC13), seven genes from HSA3 were mapped on SSC13 by fluorescence in situ hybridisation (FISH), viz. ACAA1, ACPP, B4GALT4, LTF, MYLK, PDHB and RARB. With a view to integrating this expanded comparative map with the existing SSC13 linkage map, we used the INRA-University of Minnesota porcine Radiation Hybrid panel (IMpRH) to localize more precisely and to order 15 genes on the SSC13 map, viz. ACPP, ADCY5, APOD, BCHE, CD86, DRD3, GAP43, PCCB, RAF1, RHO, SI, TF, TFRC, TOP2B and ZNF148. In this way, we were able to create an integrated map, containing 38 type I and 81 type II markers, by correlating the linkage, radiation hybrid (RH) and cytogenetic maps of SSC13. This integrated map will give us the opportunity to take maximal advantage of the comparative mapping strategy for positional candidate cloning of genes responsible for economically important traits.
A Real Collaboration Across Disciplines
Authors: Entwisle Doris R.
Published: April 2003

Over the past two decades, life course ideas have led to major changes in research on human development – changes in topics, strategies, and even the people doing it. More than any other study, Elder’s [1974] Children of the Great Depression sparked this paradigmatic shift. This study, for those few readers who have yet to see it, dealt analytically with how sharp changes in the family’s economic resources affected adolescents’ development. It was a quantitative effort to capture the effects of a unique historical event on children’s development. What Elder found was that adolescent boys from the most deprived families who worked to help their families meet the financial crisis were more successful in their own subsequent job careers than were boys from less deprived families.
Cultural Tools, Social Interaction and the Development of Thinking
Authors: Gauvain Mary
Published: April 2003

This paper discusses the role of cultural artifacts or tools in cognitive development. It examines how social interaction with more experienced partners helps children learn how to use tools that support thinking. Of particular interest is how children come to understand and use external representations, such as plans, to guide action. The discussion is illustrated by a study in which 4- to 5- and 6- to 7-year-old children and their mothers were observed as they constructed a toy by following a step-by-step action plan. The view is expressed that in order to understand cognitive development it is important to examine thinking and its development in relation to the cultural tools that support much of the intelligent action in which humans engage.
History and Life Stories
Authors: Habermas Tilmann
Published: April 2003

In response to the paper by Grob and colleagues, three aspects are highlighted. First, when analyzing the influence of history on the lives of different cohorts, it is necessary to differentiate between historical events and gradual historical change in aspects of social structure and norms. Second, the difference between 3rd person and 1st person acounts of lives (life histories vs. life stories) implies different conceptualizations of what a historical trend towards individualization implies. When analyzing life histories, individualization implies an increase in the diversity of life-courses, while when analyzing subjective conceptualizations of one’s life, individualization implies a shift of values from traditional public and other-related concerns to self-related hedonistic concerns. This more psychological approach focuses on how self-understanding is influenced by historical context. Finally, an argument is made for undertaking more detailed analyses of life stories in terms of linguistic and formal properties, in terms of age, of hind- versus foresight, and of the pragmatics of the interviewing situation.
Piaget’s Framework for a Scientific Study of Consciousness
Authors: Ferrari Michel , Pinard Adrien , Runions Kevin
Published: April 2003

While largely unacknowledged, Piaget’s views on the epistemology of consciousness presaged key positions now held by contemporary philosophers and psychologists. This paper examines Piaget’s views about two fundamental epistemological problems central to any theory of consciousness: (1) the general problem of the subject-object relationship in any type of knowing; and (2) the specific problem of the physical-mental relationship within the knowing subject. Piaget adopts a unique form of internal interactionism toward the first issue and a sophisticated form of parallelism toward the second; he aimed for an eventual integrative monism while providing compelling reasons why such a monism may always exist in name only. While his approach to these problems did not solve them, his examination of the problems – and his proposed coordination of philosophy, psychology, and neuroscience – is an important path toward consilience in the scientific study and understanding of consciousness.
Agency and Appropriation of Voice – Cultural Differences in Parental Ideas about Young Children’s Talk
Authors: Aukrust Vibeke Grøver
Published: April 2003

The problem of how children develop culturally molded individuality through talk is approached through a discussion of the concept of appropriation of voice, developed within Bakhtinian dialogical theory. The concept turns attention to otherness and ownness as processes that are simultaneously present in speaking. The problem is discussed through a study of parental ideas about otherness and ownness in talk, asking whether parents living in two different countries view their children’s talk as a process of children making others’ utterances their own or rather as a process of creating their own new utterances. The empirical examples are used to explore further the conceptual distinction between otherness and ownness in appropriation of voice, suggesting that culturally molded conceptions of agency may be at work in the construction of individuality through talk.
Relational Rationality and Children’s Interview Responses
Authors: Aronsson Karin , Hundeide Karsten
Published: April 2003

Children’s interview responses are often read monologically, as mirror reflections of their spontaneous thinking. In contrast, analyses of alignments and collaboration imply a dialogical approach. We argue that in a dialogical analysis, children’s interview responses should be read in terms of a relational rationality. Against the backdrop of such a rationality, ‘immature’ responses can be understood in terms of children’s desire to please the interviewer, and by their rational desire to align themselves with their co-participants. In contrast to the scientific rationality of Grice’s conversational maxims, relational rationality is instead discussed in terms of social relations.
Resistance to Activated Protein C, Factor V Leiden and the Prothrombin G20210A Variant in Patients with Colorectal Cancer
Authors: Paspatis Gregorios A. , Sfyridaki Aikaterini , Papanikolaou Nikolaos , Triantafyllou Kostantinos , Livadiotaki Aikaterini , Kapsoritakis Andreas , Lydataki Niki
Published: April 2003

Objective: The aim of our study was to determine the frequency of resistance to activated protein C (APC), factor V Leiden (FVL) and the prothrombin G20210A variant in patients with colorectal cancer. Methods: 74 patients with colorectal cancer and 192 colonoscopically selected controls were prospectively investigated for the presence of APC resistance, FVL and the prothrombin G20210A variant. APC resistance was measured as the ratio of activated partial thromboplastin times with and without APC (APC sensitivity ratio, APC-SR). The FVL and prothrombin G20210A variant were detected by a polymerase-chain-reaction-based technique. Results: FVL was detected in the heterozygous form in 4 of 74 cancer patients (5.4%) and in 7 of 192 controls (3.6%; p > 0.5, odds ratio: 1.51). After excluding patients and controls with FVL, APC-SR was below 2 in 6 of 70 cancer patients (8.5%) and in 1 of 185 controls (0.5%; p < 0.01, odds ratio: 17.25), and the mean value of APC-SR was significantly lower in cancer patients than the respective level of controls (2.8 vs. 3.7, p < 0.001). The G20210A mutation in the prothrombin gene was found in the heterozygous form in 2 of 74 patients with colorectal cancer (2.7%) and in 5 of 192 colonoscopically control subjects (2.6%; p > 0.5, odds ratio: 1.03). Conclusions: These findings suggest that patients with colorectal cancer have a high frequency of resistance to APC but no significant differences in the frequency of the FVL or G20210A mutation of the prothrombin gene compared to colonoscopically selected controls.
Disease Transmission by Blood Products: Past, Present and Future
Authors: Murphy William G.
Published: April 2003

Transfusion of blood and blood products has been associated with transmission of infectious agents. However, it is probable that blood products are currently very safe and that pooled virus-inactivated products from remunerated donors are now safer than untreated single voluntary donor components. Although the transmission events of the past and the present are reasonably well understood, reliance on a linear approach to predict safety in the future is open to criticism. Indeed, it was not possible to predict the extent or consequences of the AIDS epidemic or of hepatitis C transmission. Moreover, although variant Creutzfeldt-Jakob disease (vCJD) may not be transmitted to any large extent by transfusion of manufactured blood products, this will be due more to good fortune than good judgement – this agent could have escaped the screening, testing and eradication methods on which current confidence in blood product safety depends. Similarly, the emergence of a highly resistant non-enveloped virus, or even of another previously unrecognised disease-causing agent, could result in new threats from transfusion of blood components and products. The ecology of blood transfusion is exquisitely sensitive to variations in starting conditions, a situation typical of a chaotic rather than a linear system. Seemingly trivial events, often apparently unrelated to blood transfusion, have had enormous consequences in this field. Whatever the events that introduced simian immunodeficiency virus to humans or scrapie to cattle, they were a long way from those involved in the manufacture of blood products. In such a setting, reliance on methods that deal effectively with known threats (such as encapsulated viruses and bacteria) without adequate investigation and management of the intrinsic sensitivity to unpredictable events, leaves open the possibility of further infections emerging in the future. It is this reality that will ultimately result in the eradication of the transfusion of donor-derived blood and blood products in the developed world. In addition, all infections with a long disease-free incubation period in the host that can be transmitted in blood will eventually be over-expressed in groups that are exposed to blood either recreationally or professionally. As in the past, this could have occurred before testing or decontamination processes have been developed for emerging pathogens. Failure to be able to rely on completely risk-free donors, in both the voluntary and non-voluntary sides of the blood industry, continues to offer the potential for the transmission of infectious diseases in the future.
Recombinant Factor VIIa in the Management of Surgery and Acute Bleeding Episodes in Children with Haemophilia and High-Responding Inhibitors
Authors: Smith Owen P.
Published: April 2003

The development of inhibitors to therapeutic factor concentrates in children with haemophilia A or B is a troublesome complication of factor replacement therapy. Immune tolerance protocols have been developed to eliminate the inhibitors, and these are successful in approximately 80% of children. However, acute bleeding episodes require treatment with a factor (F)VIII or FIX bypassing agent to prevent an anamnestic rise in the inhibitor level before starting immune tolerance. In addition, central venous access is necessary to help parents administer frequent, high dose factor concentrate. In view of the benefits of rFVIIa seen in adults, a study has been carried out on the use of this agent as haemostatic cover in children with severe FVIII or FIX deficiency with high responding inhibitors. Information was obtained retrospectively from the National Children’s Hospital, Dublin and Great Ormond Street Hospital, London. Twelve children aged 1–16 years were treated successfully with rFVIIa to prevent surgical bleeding in 20 surgical procedures. Minor post-operative haematomata developed in 2 of 20 cases after regular rFVIIa therapy had been discontinued. In both cases, resolution of bleeding occurred after a short course of rFVIIa. Three children experienced a total of six life- or limb-threatening bleeds. All bleeding episodes resolved with regular rFVIIa treatment, although topical fibrin glue was needed in one child with a frenulum tear. The rFVIIa therapy was well tolerated and there was no evidence of any treatment-related complications. In conclusion, rFVIIa is the treatment of choice for the management of surgery and acute life- or limb-threatening bleeding in children with haemophilia and high responding inhibitors.
Determinants of Protein Turnover in Health and Disease
Authors: Newby F. David , Price S. Russ
Published: April 2003

Protein synthesis, protein degradation, and amino acid oxidation are tightly regulated to preserve lean body mass in healthy individuals. An adaptative response to a reduction in dietary protein in normal adults is decreased branched-chain amino acid oxidation which increases the availability of amino acids. In nephrosis, reduced branched-chain amino acid oxidation decreases amino acid requirements and helps to compensate for urinary protein loss. Conversely, uremia and other catabolic diseases are associated with muscle wasting resulting from activation of the ubiquitin-proteasome proteolytic pathway and branched-chain ketoacid dehydrogenase, the rate-limiting enzyme for branched-chain amino acid catabolism. By understanding the processes responsible for muscle wasting in catabolic states, therapeutic interventions may be designed to improve protein balance.
Molecular and Cell Biology of TGF-β
Authors: Roberts Anita B.
Published: April 2003

The TGF-βs are a remarkable set of peptides consisting of three highly homologous isoforms, TGF-β 1, 2, and 3. Distinguished initially for their ability to inhibit the growth of most epithelial and hematopoietic cells and to regulate the production of extracellular matrix by mesenchymal cells, these peptides are now known to act via autocrine, paracrine, and endocrine modes to control a wide variety of developmental processes and to play key roles in the pathogenesis of many diseases including especially fibrotic diseases, parasitic diseases, autoimmune diseases, and carcinogenesis. The activity of these peptides is under tight control by processes including regulation of the expression of the isoforms and their receptors and of the trafficking and activation of their latent forms.
Lessons from TGF-β Transgenic Mice
Authors: Böttinger Erwin P. , Kopp Jeffrey B.
Published: April 2003

Aberrant expression of TGF-β and/or receptor/signaling function is present in a wide variety of disease processes. Overexpression of TGF-β isoforms in transgenic mice using tissue-specific promoters has provided model systems to study the effects of increased activity of TGF-β in the intact organism. We will review the pertinent features of some of these models, and discuss new insights provided by these studies into regulation and role of TGF-β in health and disease.
Management of Hypertension in Renal Disease
Authors: Marcantoni Carmelita , Oldrizzi Lamberto , Rugiu Carlo , Maschio Giuseppe
Published: April 2003

The treatment of systemic hypertension in chronic renal disease is now mostly based on the administration of drugs which are able to reduce proteinuria and to slow down the progressive functional deterioration. Angiotensin-converting-enzyme inhibitors (ACEI), which lower both proteinuria and blood pressure, have emerged as drugs of choice in proteinuric patients with either normal renal function or mild to moderate chronic renal failure. In non proteinuric nephropathies no controlled studies exist demonstrating the superiority of ACEI over other drugs. In these conditions calcium antagonists might also be used. The approach to patients with hypertension and renal disease should always take into consideration the quality of the results that are to be achieved. If the aim is to control blood pressure and to protect other organs at risk, then a variety of drugs can be used. If the aim is to reduce proteinuria and slow down progression, then ACEI, possibly associated with calcium antagonists, are the drugs of choice.
A Low Calcium Environment Enhances AP-1 Transcription Factor-Mediated Gene Expression in the Development of Osteoblastic MC3T3-E1 Cells
Authors: Deyama Ayako , Deyama Yoshiaki , Matsumoto Akira , Yoshimura Yoshitaka , Nishikata Makoto , Suzuki Kuniaki , Totsuka Yasunori
Published: April 2003

Animals fed a low calcium diet develop hypocalcemia and osteoporotic bone. Earlier we conjectured that a low calcium environment might be one of the factors causing abnormalities in hard tissues. Osteoblastic MC3T3-E1 cells (E1 cells) undergo a process of proliferation and differentiation and then produce small mineralized nodules. In this study, we examined the effects of a low calcium environment on osteoblast-like cells cultured with 10% fetal bovine serum and ascorbic acid. Under the culture condition, nodules with characteristics of normal bone appeared by day 30 regardless of the calcium conditions. However, the low calcium environment enhanced the mRNA expressions of c-fos, c-jun and osteocalcin, a specific marker of the osteoblast phenotype. And the exposure to the low calcium medium inhibited the formation of bone nodules. We further studied the differential expressions of c-fos and c-jun in relation to their responses to serum as a function of phenotypic development in the low calcium environment. Both c-fos and c-jun expressions were highly activated by treatment with epidermal growth factor (EGF), but the magnitude of activation was significantly larger under the low calcium condition than the normal condition at each stage. In addition, DNA-binding activities of activating protein-1 (AP-1), Fos/Jun family dimers, were also accelerated by EGF treatment in the low calcium environment. Our findings suggested that osteocalcin, a bone formation marker, c-fos and c-jun genes, and family protein products (AP-1) interacted to restore the normal cell function which deteriorated in the low calcium environment.
Apolipoprotein C-III, Hypertriglyceridemia and Triglyceride-Rich Lipoproteins in Uremia
Authors: Moberly James , Attman Per-Ola , Samuelsson Ola , Johansson Ann-Cathrine , Knight-Gibson Carolyn , Alaupovic Petar
Published: April 2003

Apolipoprotein C-III (ApoC-III) plays an important role in the metabolism of triglyceride-rich lipoproteins and is known to be elevated in patients with uremia. To investigate the role of apoC-III in uremic dyslipidemia, we examined apoC-III, triglyceride levels and lipoprotein particles containing both apoB and apoC-III (LP-Bc) in 27 uremic patients prior to dialysis (predialysis), 30 patients on hemodialysis (HD) and 31 patients on peritoneal dialysis (PD). All three groups of patients had elevated levels of plasma apoC-III (20±7 mg/dl for predialysis, 18±5 for HD and 22±8 for PD, compared to 11±3 mg/dl for control subjects [p<0/01 for all comparisons]). ApoC-III was positively correlated with plasma triglycerides in PD patients (r = 0.86, p<0.0001), HD patients (r = 0.67, p<0.0001) and predialysis patients (r = 0.60, p<0.001) as well as in all patients combined (r = 0.75, p<0.0001). ApoC-III was also positively correlated with levels of LP-Bc in all three groups of patients, although this correlation was less strong (r = 0.46, p<0.0001 for all patients combined). In predialysis and PD patients, the majority of apoC-III was found in heparin precipitable lipoproteins, whereas the majority of apoC-III in HD patients was found in HDL, indicating less efficient lipolysis in predialysis and PD patients in comparison with HD. These data support the hypothesis that the elevation of apoC-III in uremia can alter the metabolism of triglyceride-rich lipoproteins, leading to an elevation in triglycerides and LP-Bc. Understanding the mechanism(s) of elevated apoC-III in uremia may help to clarify the causes of uremic dyslipidemia.
Pathophysiology and Clinical Importance of Hyperhomocysteinemia: Clinical Intervention Studies
Authors: Sunder-Plassmann Gere , Födinger Manuela
Published: April 2003

Hyperhomocysteinemia is a cardiovascular disease risk factor in the general population and in patients with renal failure. This article summarizes the results of recent total homocysteine-lowering intervention studies in individuals without renal failure and in patients with renal failure. Although almost all of the published studies mainly focused on the total homocysteine-lowering effect and not on cardiovascular disease outcomes of folic acid and vitamin therapy, recent work has gained important insights into this area of developing concern.
Nonclassical Effects of 1α,25-Dihydroxyvitamin D3 and Its Analogs
Authors: Verstuyf A. , Verlinden L. , Segaert S. , van Etten E. , Mathieu C. , Bouillon R.
Published: April 2003

The activated form of vitamin D3, 1α,25(OH)2D3, not only plays a central role in bone and calcium metabolism but has also potent antiproliferative and prodifferentiating effects. Moreover, the combined presence of 25(OH)D3-1α-hydroxylase as well as the vitamin D receptor in several tissues introduced the idea of a paracrine role for 1α,25(OH)2D3. By introducing chemical modifications into the flexible parent molecule 1α,25(OH)2D3, a whole generation of vitamin D analogs was created. Due to a clear dissociation of the antiproliferative and prodifferentiating effects from calcemic effects, these analogs can be used not only for the treatment of bone disorders but also for non-classical applications.
The Vestibular Nuclei and Vestibuloreticular Connections in the Mallard (Anas platyrhynchos L.)
Authors: Tellegen Annet J. , Arends Joop J.A. , Dubbeldam Jacob L.
Published: April 2003

The vestibular apparatus provides information about the position and movements of the head. Craniocervical muscles position the head with respect to the upper part of the neck. Motoneurons innervating these muscles are located in the supraspinal nucleus and ventral horn of the rostral cervical cord. Premotor neurons of craniocervical muscles have been found in the medial two-thirds of the medullary reticular formation: the ventromedial part of the parvocellular reticular formation and the gigantocellular reticular formation. In the present study, projections from vestibular nuclei upon craniocervical premotor neurons were investigated using anterograde and retrograde tracers. Vestibulospinal fibers run bilaterally in the medial vestibulospinal tract and ipsilaterally in the lateral vestibulospinal tract. Vestibuloreticular projections are mainly ipsilateral, and originate from the n. vestibularis lateralis pars ventralis and pars dorsalis, and from the n. vestibularis descendens. Terminal labeling is found in the border zone between the parvocellular and gigantocellular reticular formation. These projections show that in addition to direct bilateral vestibulo-craniocervical projections an indirect vestibular pathway to craniocervical motor nuclei exists. The direct pathway probably is the neural substrate for the vestibulocollic reflex, whereas the vestibular projection upon the reticular formation might influence head orientation during various kinds of activities, such as pecking, preening and so on.