bluuebunny/crossref_metadata_2025 huggingface dataset:
Ribosome biogenesis in man: Current views on nucleolar structures and function
Authors: Schwarzacher H.G. , Mosgoeller W.
Published: April 2003

Nucleoli develop when preribosomes are synthesized at the chromosomal nucleolar organizer regions. Typically they consist of at least three nucleolar subcompartments, the fibrillar center (FC), the dense fibrillar component (DF), and the granular component (GC). The understanding of the functional arrangements of these subcompartments relates to aspects in cell biology, pathology, and virus research. In the present review morphological studies are discussed in the light of molecular findings. The available data confirm the hypothesis that rDNA transcription is connected with the DF but not necessarily with the presence of an FC. Within the DF, rDNA transcription is restricted to foci, possibly representing single transcribing genes. FCs may serve to store inactive transcription factors, to initiate rDNA transcription, and may provide structural support for transcription. The GC can be interpreted as a collection of maturing preribosomes. More recently the nucleolar subcompartments were focused on in the context of virus research and tumor biology.
Mutagen sensitivity of human lymphoblastoid cells with a BRCA1 mutation in comparison to ataxia telangiectasia heterozygote cells
Authors: Speit G. , Trenz K. , Schütz P. , Bendix R. , Dörk T.
Published: April 2003

Our previous results indicated a close relationship between the presence of a BRCA1 mutation in lymphocytes and hypersensitivity for the induction of micronuclei by gamma irradiation and hydrogen peroxide (H2O2). Comparative investigations with the comet assay (single-cell gel electrophoresis) suggested a normal rate of damage removal and pointed to a disturbed fidelity of DNA repair as a direct or indirect consequence of a BRCA1 mutation. We now wanted to see whether similar results could be obtained with lymphoblastoid cell lines (LCLs) and whether such permanent cells are suitable as a model for the investigation of mechanisms involved in mutagen sensitivity. Our results show that LCLs with a BRCA1 mutation are also hypersensitive to the chromosome-damaging effects of gamma irradiation or H2O2, as revealed by the micronucleus test. Interestingly, LCLs heterozygous for an ataxia telangiectasia (AT) mutation have similar characteristics as BRCA1 cells with respect to the induction and repair of DNA damage induced by either gamma irradiation or H2O2. However, caffeine enhanced the induction of micronuclei by gamma irradiation only in normal and heterozygous AT cells but not in BRCA1 cells, thus indicating a difference in the pathways leading to mutagen sensitivity in cells with a BRCA1 or an AT mutation. Our results suggest that caffeine could be useful in discriminating AT heterozygotes from carriers of a BRCA1 mutation, as well as BRCA1 mutation carriers from normal individuals.
EST mining of the UniGene dataset to identify retina-specific genes
Authors: Stöhr H. , Mah N. , Schulz H.L. , Gehrig A. , Fröhlich S. , Weber B.H.F.
Published: April 2003

Age-related macular degeneration (AMD) is a multifactorial disorder affecting the visual system with a high prevalence among the elderly population but with no effective therapy available at present. To better understand the pathogenesis of this disorder, the identification of the genetic factors and the determination of their contribution to AMD is needed. Towards this goal, we are pursuing a strategy that makes use of the EST data processed in the UniGene database and aims at the generation of a comprehensive catalogue of genes preferentially active in the human retina. Subsequently, these genes will be systematically assessed in AMD. We performed a retina EST sampling and obtained a total of 673 clusters containing only retina ESTs as well as 568 clusters with at least 30% of the ESTs in each cluster originating from retina cDNA libraries. Of these, 180 representative EST clusters with varying retina and non-retina EST contents were analyzed for their in vitro expression. This approach identified 39 transcripts with retina-specific expression. One of these genes (C18orf2) mapping to chromosome 18 was further characterized. Multiple C18orf2 transcripts display a complex pattern of differential splicing in the human retina. The various isoforms encode hypothetical polypeptides with no homologies to known proteins or protein motifs.
The human Y chromosome derives largely from a single autosomal region added to the sex chromosomes 80–130 million years ago
Authors: Waters P.D. , Duffy B. , Frost C.J. , Delbridge M.L. , Graves J.A.M.
Published: April 2003

Mapping of human X-borne genes in distantly related mammals has defined a conserved region shared by the X chromosome in all three extant mammalian groups, plus a region that was recently added to the eutherian X but is still autosomal in marsupials and monotremes. Using comparative mapping of human Y-borne genes, we now directly show that the eutherian Y is also composed of a conserved and an added region which contains most of the ubiquitously expressed Y-borne genes. Little of the ancient conserved region remains, and the human Y chromosome is largely derived from the added region.
Chromosomal distribution, localization and expression of the human endogenous retrovirus ERV9
Authors: Svensson A-C. , Raudsepp T. , Larsson C. , Di Cristofano A. , Chowdhary B. , La Mantia G. , Rask L. , Andersson G.
Published: April 2003

ERV9 is a class I family of human endogenous retroviral sequences. Somatic cell hybrid genomic hybridization experiments using a mono-chromosomal panel indicate the presence of approximately 120 ERV9 loci in the human genome distributed on most chromosomes. Fluorescence in situ hybridization (FISH) using an ERV9 cDNA probe containing gag, pol and env sequences, verified this observation and a consistent signal was found at the chromosome region 11q13.3→q13.5. By analysis of a panel of radiation hybrids, an ERV9 locus was mapped to within a 300-kbp region at the chromosome site 11q13. The marker cCLGW567 and the locus MAP3K11/D11S546 centromeric and telomeric flanked it, respectively. Northern blot analysis, using an ERV9 LTR probe, indicated that most normal tissues examined expressed low abundant ERV9 LTR driven mRNAs of various sizes. The most prominent expression was found in adrenal glands and testis. However, the level of expression varied in the same tissues among different individuals indicating that ERV9 mRNA expression probably is inducible in certain tissues or at various cell stages.
Mapping of genes and transcribed sequences in a gene rich 400-kb region on human chromosome 11p15.1→p14
Authors: Caldwell G.M. , Eddy R.L. , Day C.D. , Haley L.H. , Cooper P.R. , Sait S.S.J. , Hejtmancik F. , Smith R.J.H. , Morton C.C. , Higgins M.J. , Shows T.B.
Published: April 2003

We have identified a number of transcribed sequences within a 400-kb interval on chromosome 11p15.1→ p14. Six genes and 13 novel transcripts including ESTs, cDNAs and exons have been identified and assigned to this region. Comparison of mRNA sequence with genomic sequence has enabled us to determine the exon/intron structure of four of the genes (NUCB2, PIK3C2A, RPS13 and OR7E14P).
An ATP-binding cassette gene (ABCG5) from the ABCG (White) gene subfamily maps to human chromosome 2p21 in the region of the Sitosterolemia locus
Authors: Shulenin S. , Schriml L.M. , Remaley A.T. , Fojo S. , Brewer B. , Allikmets R. , Dean M.
Published: April 2003

We characterized a new human ATP-binding cassette (ABC) transporter gene that is highly expressed in the liver. The gene, ABCG5, contains 13 exons and encodes a 651 amino acid protein. The predicted protein is closely related to the Drosophila white gene and a human gene, ABCG1, which is induced by cholesterol. This subfamily of genes all have a single ATP-binding domain at the N-terminus and a single C-terminal set of transmembrane segments. ABCG5 maps to human chromosome 2p21, between the markers D2S117 and D2S119. The abundant expression of this gene in the liver suggests that the protein product has an important role in transport of specific molecule(s) into or out of this tissue.
cDNA cloning, chromosome assignment, and genomic structure of a human gene encoding a novel member of the RBM family
Authors: Stover C. , Gradl G. , Jentsch I. , Speicher M.R. , Wieser R. , Schwaeble W.
Published: April 2003

We have cloned and characterised a novel human gene mapping to chromosome 20q11.2. A partial transcript was initially isolated from a human cDNA library transcribed from RNA of the colon carcinoma cell line T-84. In order to determine the full coding sequence of this novel mRNA, we isolated seven cDNA clones from a human cDNA library transcribed from RNA of the acute monocytic leukemia cell line THP1 by colony hybridization. On Northern blot analysis of four human cell lines, the cDNAs isolated hybridize with an abundantly expressed mRNA species of 3.5 kb. A full-length cDNA transcript of this novel mRNA has an open reading frame of 2,796 bp encoding a protein with a calculated molecular weight of 97 kDa. Two repetitive structural consensus motifs are contained within the deduced protein sequence, namely five distinct RNA binding motifs and two proline rich regions. The derived protein sequence also contains putative transmembrane domains. These structural motifs identify this novel protein as a member of an expanding protein family containing RNA binding motifs (RBM). As seen from recently completed sequence of the genomic area encoding this novel mRNA by the Sanger Centre Human Genome Project, the coding region of this gene, RBM12, is intronless.
Identification and isolation of a full-length clone of mouse GMFB (Gmfb), a putative intracellular kinase regulator, differentially expressed in telencephalon
Authors: Bourgeois F. , Guimiot F. , Mas C. , Bulfone A. , Levacher B. , Moalic J.M. , Simonneau M.
Published: April 2003

We identified new transcribed sequences, using a differential display paradigm to select genes expressed in proliferating neuroblasts from mouse telencephalon at 10 days of embryonic development. In this systematic search, we isolated a 361-bp partial 3′ untranslated region (3′ UTR) homologous to the 3′ UTR of the human gene encoding a putative intracellular kinase regulator, glia maturation factor beta (GMFB). We cloned a full-length, 4,311-bp mouse cDNA containing a 270-bp 5′ UTR, a 3,615-bp 3′ UTR, and an open reading frame of 426 nucleotides encoding a putative 142 amino-acid protein, identical to human GMFB, with the exception of two amino acids. This 4.3-kb transcript is present in a variety of adult tissues and is developmentally regulated as shown by Northern blot analysis. Differential expression in telencephalon was demonstrated by quantification of radioactive relative RT-PCR and confirmed by in situ hybridization. The isolation of this full-length clone of mouse Gmfb should facilitate investigation of the intracellular mechanisms involved in the development of telencephalon.
Isolation, characterization, and chromosome mapping of a human A-C1 Ha-Ras suppressor gene (HRASLS)
Authors: Ito H. , Akiyama H. , Shigeno C. , Nakamura T.
Published: April 2003

Recently, we cloned a cDNA encoding a novel mouse protein, named A-C1, by differential display between two mouse cell lines, embryonic fibroblast C3H10T1/2 and chondrogenic ATDC5. Mouse A-C1 has homology with a ras-responsive gene, rat Ha-rev107 (Hrasls), and modulates a Ha-ras-mediated signaling pathway. Here, we report a cDNA encoding a human homolog of mouse A-C1. The deduced amino acid sequence of human A-C1 consists of 168 amino acids, and shows 83% identity with that of mouse A-C1. Human A-C1 mRNA was expressed in skeletal muscle, testis, heart, brain, and thyroid in vivo. Moreover, expression of human A-C1 mRNA was detected at a high level in human osteosarcoma-derived U2OS cells in vitro. By FISH analysis the human A-C1 gene (HRASLS) was mapped to human chromosome 3q28→ q29.
Delineation of a 150-kb breakpoint cluster in benign thyroid tumors with 19q13.4 aberrations
Authors: Belge G. , Rippe V. , Meiboom M. , Drieschner N. , Garcia E. , Bullerdiek J.
Published: April 2003

Structural rearrangements involving the long arm of chromosome 19 characterize a cytogenetic subgroup of benign thyroid tumors and constitute one of the most frequent specific chromosome abnormalities in epithelial tumors. Recently, we have been able to narrow down the breakpoint region affected in two cell lines to a region covered by a single PAC clone. Close to that region a candidate gene has been identified which we tentatively referred to as RITA (Rearranged In Thyroid Adenomas) now named ZNF331 according to HUGO nomenclature. However, the results had been obtained on two cell lines only making it necessary to extend the studies to a larger number of tumors including primary material. Herein, we have used four further primary tumors showing translocations involving 19q13 for fluorescence in situ hybridization (FISH) mapping studies using a variety of molecular probes from a 470-kbp cosmid/BAC contig. Ten new STSs were characterized and physically mapped within an EcoRI restriction map. The results enabled us to define an approximately 150-kbp breakpoint cluster region of the 19q13 aberrations in benign thyroid tumors flanked by two newly established STS markers.
Mouse Sox8 is located between, not within,the t-complex deletions tw18 and th20 on chromosome 17
Authors: Schepers G. , Koopman ,P.
Published: April 2003

The SOX family of developmental transcription factors is known to play critical roles in cell lineage specification, fate determination and differentiation during development in diverse phyla. Their importance is underscored by their involvement in a number of human diseases and mouse mutants, and by targeted mutation in mice. SOX8 is broadly expressed during development and is located on human chromosome 16p and within the t-complex on mouse chromosome 17, in the vicinity of two mutations tw18 and th20. Here we analyse mutant genomic DNA to show that the Sox8 gene locus lies outside the deletion regions of both tw18 and th20 and between these deletions. These data exclude Sox8 from contributing to the tw18 and th20 phenotypes, and provide an additional marker for structural characterization of this complex genomic region.
Telomere shortening in Fanconi anaemia demonstrated by a direct FISH approach
Authors: Hanson H. , Mathew C.G. , Docherty Z. , Mackie Ogilvie C.
Published: April 2003

Analysis of telomere status in patients with Fanconi anaemia (FA) has previously been carried out by measurement of telomere restriction fragment (TRF) length by Southern blotting and densitometry. Results from these studies indicated that FA patients had significant reduction in telomere length compared with age-matched controls. This paper confirms and extends these findings using a direct FISH technique, which showed that 15 out of 16 FA patients had increased loss of telomere signals compared with controls. In 12 out of the 16 patients, decrease in telomere signal intensity could also be detected using a Q-FISH approach.
Meningioma: a cytogenetic model of a complex benign human tumor, including data on 394 karyotyped cases
Authors: Zang K.D.
Published: April 2003

Meningioma is the most frequent tumor of neuroectodermal origin in humans. It is usually benign. Only a minority of cases shows progression to an anaplastic tumor (WHO grade II and III). Meningioma is generally a sporadic tumor. Multiple and familial cases are rare and mostly associated with (hereditary) neurofibromatosis 2 (NF2). Meningiomas show an unexpectedly high recurrence rate. Also, completely removed low-grade tumors can recur. Recurrence and multiplicity are correlated with the formation of a peritumoral edema. On the cytogenetic level, meningioma is the best-studied tumor in humans. Grade I tumors show either uniform monosomy 22 or a diploid karyotype. The majority of high-grade, but only a minority of low-grade, meningiomas show loss of merlin, a cytoskeleton-cytoplasm-linker protein. Merlin is the product of the NF2 gene located on chromosome 22. A second tumor suppressor gene on chromosome 22 has not yet been detected. In contrast to other solid tumors, progression of meningiomas is correlated with increasing hypodiploidy, showing characteristic clonal evolutions that mostly include chromosomes 14, 18, and 19 and, more rarely, 6 and 10. Structural aberrations are infrequent, except for the loss of the short arm of chromosome 1, which appears to be the decisive step for anaplastic growth. Comparative histochemical and molecular cytogenetic studies point to the alkaline phosphatase gene (ALPL, liver-bone-kidney type) located on 1p36.1→p34 as a candidate tumor suppressor gene. A model is proposed that tries to explain – with a minimum number of essential steps – the origin, progression, infiltration, and recurrence of meningiomas.
Reconstruction of the female Gorilla gorilla karyotype using 25-color FISH and multicolor banding (MCB)
Authors: Mrasek K. , Heller A. , Rubtsov N. , Trifonov V. , Starke H. , Rocchi M. , Claussen U. , Liehr T.
Published: April 2003

The origin of the human and great ape chromosomes has been studied by comparative chromosome banding analysis and, more recently, by fluorescence in situ hybridization (FISH), using human whole-chromosome painting probes. It is not always possible, however, to determine the exact breakpoints and distribution or orientation of specific DNA regions using these techniques. To overcome this problem, the recently developed multicolor banding (MCB) probe set for all human chromosomes was applied in the present study to reanalyze the chromosomes of Gorilla gorilla (GGO). While the results agree with those of most previous banding and FISH studies, the breakpoints for the pericentric inversion on GGO 3 were defined more precisely. Moreover, no paracentric inversion was found on GGO 14, and no pericentric inversions could be demonstrated on GGO 16 or 17.
Chromosomal evolution in the vlei rat, Otomys irroratus (Muridae: Otomyinae): a compound chromosomal rearrangement separates two major cytogenetic groups
Authors: Rambau R.V. , Elder F.F.B. , Robinson T.J.
Published: April 2003

G- and C-banding delimits two cytogenetic groups within the vlei rat, Otomys irroratus. One has a diploid number of 2n = 24, resulting from a centric fusion of chromosomes 7 and 12 of the O. irroratus standard coupled with a tandem fusion to chromosome 8. The second has a diploid number of 2n = 28, lacks the compound chromosome, and appears to have a far wider geographic distribution within South Africa. Additionally, the two groups differ through the presence of cytotype-specific heterozygous centric fusions and one to three B chromosomes which appear as floating polymorphisms in the 2n = 28 complex.
Comparative FISH mapping of human cDNA clones to chromosomes of the musk shrew (Suncus murinus, Insectivora)
Authors: Matsubara K. , Ishikawa A. , Kuroiwa A. , Nagase T. , Nomura N. , Namikawa T. , Matsuda Y.
Published: April 2003

Forty-one cDNA clones of human functional genes were newly mapped to chromosomes of the musk shrew (Suncus murinus, Insectivora) by fluorescence in situ hybridization, and a comparative cytogenetic map of 51 genes, including 10 genes reported in our previous study, was constructed between human (HSA) and musk shrew (SMU) chromosomes. In this comparative map, the 51 genes localized to human autosomes, except HSA 8, 16, and 20, were mapped to 15 shrew autosomes, except SMU 4, 16, 17 and 18. Twelve conserved segments were identified between human and shrew chromosomes, and six segments among the musk shrew, human, and mouse. Our results defined the presence of at least one inversion and several interchromosomal rearrangements that occurred during evolution after the two species diverged from a common ancestor. Localization of three major histocompatibility complex (MHC) genes to shrew chromosome 3 suggested that the MHC genes of the musk shrew are located in a cluster on chromosome 3. The cytogenetic map constructed in this study is the first cytogenetic map with many functional genes in insectivore species. This approach provides clues for clarifying the chromosomal evolution in this order.
Genetic abnormalities in a pre and post-chemotherapy hepatoblastoma
Authors: Mullarkey M. , Breen C.J. , McDermott M. , O’Meara A. , Stallings R.L.
Published: April 2003

Comparative genomic hybridization (CGH) analysis was performed on both a pre- and post-chemotherapy hepatoblastoma from a 24-month-old female patient. The diagnostic sample obtained from a tru-cut biopsy was a mixed epithelial-mesenchymal tumor with both fetal and embryonal patterns present. In contrast, the post-chemotherapy tumor exhibited a prominent anaplastic large cell population focally reminiscent of pleomorphic hepatocellular carcinoma (HCC). CGH analysis indicated that there were similarities as well as differences in the gains and losses of genetic material in each tumor. The diagnostic sample had gains of chromosome 1q, 2, 2(q31q33), 7, 8q, 12(q15q22), 17q and 20 material, while the post-chemotherapy tumor had gains of 1q, 2, 7, 8q, 10, 17q and 20 material. In addition, the pre- and post-chemotherapy samples may have incurred loss of chromosome 17p material. The main differences between the two samples involved localized gain of 2(q31q33) and 12(q15q22) in the pre-chemotherapy sample, and gain of chromosome 10 material in the post-chemotherapy tumor. The patient subsequently developed metastatic nodules in her lungs, the histology of which was identical in pattern to the diagnostic pattern, and appeared to have localized gain of 2(q31q33) and 12(q15q22). These results are consistent with published results that gain of chromosome 8q and 20 are associated with an unfavorable prognosis.
Non-random chromosomal distribution of SSLPs: systematic assessment using a novel genetic linkage map between two closely related rat strains
Authors: Gigante B. , Rubattu S. , Zee R.Y.L. , Volpe M. , Lindpaintner K.
Published: April 2003

Simple sequence length polymorphisms (SSLPs) are a widely used tool for genetic studies in humans and model animals. Experimental crosses among closely related strains that differ primarily in the trait that is to be mapped carry the advantage of avoiding co-segregation of potentially confounding traits. However, their realization is encumbered by the limited availability of newly arisen informative SSLPs among such strains. Here we report the establishment of a genome-wide SSLP panel for the spontaneously hypertensive rat (SHR) and its close relative, the stroke-prone SHR (SHRSP), consisting of a total of 273 polymorphic markers that were found among 2,734 rat SSLPs screened. In addition to limitations in numbers, we also found the distribution of informative markers to be heterogeneous, with clustering and paucity of informative markers, respectively, in particular regions. Notably, the majority of regions thus identified was also seen when we examined an unrelated set of strains from the literature, indicating, on a more generic level, the presence of mutagenically more and less stable genomic regions.
Cytogenetics of collared lemmings (Dicrostonyx groenlandicus). II. Meiotic behavior of B chromosomes suggests a Y-chromosome origin of supernumerary chromosomes
Authors: Berend S.A. , Hale D.W. , Engstrom M.D. , Greenbaum I.F.
Published: April 2003

The patterns of synapsis and chiasma formation of the B chromosomes of male collared lemmings (Dicrostonyx groenlandicus) were analyzed by light and electron microscopy and compared to expectations for various hypotheses for the intragenomic origin of supernumerary chromosomes. Pachytene analysis revealed a variety of synaptic configurations including B-chromosome univalents, bivalents and trivalents. In approximately one-half of the pachytene nuclei examined, B chromosomes were in synaptic associations with the normally unpaired portion of the Y chromosome. The B-chromosome configurations at pachynema, including those involving the Y chromosome, were maintained into diakinesis and metaphase I. The meiotic behavior of the B chromosomes was inconsistent with their derivation from centric-fusion products, isochromosome formation, small-autosome polysomy, or the X chromosome. However, the frequent synapsis and apparent recombination between B chromosomes and the Y chromosome implicate this sex chromosome as a possible source of the B chromosomes in collared lemmings.
Characterization and comparative mapping of the porcine CTSL gene indicates a novel synteny between HSA9q21→q22 and SSC10q11→q12
Authors: Spötter A. , Drögemüller C. , Kuiper H. , Brenig B. , Leeb T. , Distl O.
Published: April 2003

Cathepsin L (CTSL) is a lysosomal cysteine protease with potent elastase and collagenase activities. Its high activity in the uterine lumen during the period of placental attachment has led to speculation that CTSL may play an important role during embryonic implantation in the pig. Cathepsins have also been implicated in blastocyst implantation in other species like cat, rat and man. We isolated a PAC clone containing the porcine CTSL gene and determined the complete DNA sequence of the gene, which spans about 5.6 kb and consists of eight exons. The CTSL transcript encodes a primary peptide of 334 amino acids sharing 73–78% identity with other mammalian cathepsin L precursor proteins. Based on fluorescence in situ hybridization and radiation hybrid mapping, the porcine CTSL gene was assigned to chromosome 10q11→ q12.
Guinea Pig Gonadotropin-Releasing Hormone: Expression Pattern, Characterization and Biological Activity in Rodents
Authors: Montaner Alejandro D. , Mongiat Lucas , Lux-Lantos Victoria A. , Warby Carol , Chewpoy Brad , Bianchi María S. , Libertun Carlos , Rivier Jean E. , Sherwood Nancy M. , Somoza Gustavo M.
Published: April 2003

Gonadotropin-releasing hormone (GnRH) is a decapeptide widely known for its role in regulating vertebrate reproduction by serving as a signal from the hypothalamus to pituitary gonadotropes. The first form of GnRH to be identified was isolated from mammals (mGnRH) and the same form has been reported for all mammals studied, which includes marsupials and placental mammals. Later, another variant, chicken GnRH-II (cGnRH-II) was shown to be expressed together with mGnRH in the brains of all jawed vertebrates, including mammals such as rats, monkeys and humans. Our objective was to characterize a third form of GnRH that was isolated previously as mRNA from guinea pigs (gpGnRH), but has not been reported for any other mammal to date. Furthermore, the gonadotropic activity of gpGnRH has not been fully characterized. Our results, using chromatographical and immunological methods, show for the first time that gpGnRH is expressed together with mGnRH in some rodents (wild guinea pig and capybara), but not in others (mouse and hamster). Also, the gonadotropic activity of gpGnRH and mGnRH was tested in two different rat cell culture systems. Although there have been reports that the salmon(s) form of GnRH is present in mammals, we did not detect sGnRH in capybara, wild guinea pigs, hamsters, rats or mice. Taken together with previous reports, the present results support the idea that the expression of multiple GnRH variants in a single species is a common pattern in most vertebrate groups.
Growth Factors:Future Prospects in Renal Failure
Authors: Fouque Denis
Published: April 2003

Chronic renal failure is associated with an abnormal growth hormone/insulin-like growth factor-1 axis. In addition, nutritional status strongly regulates this axis. Because these hormones are involved in growth in children and maintenance of a normal body composition in adults, experimental and clinical studies have tested the metabolic effects of these recombinant growth factors. Various conditions in which these growth factors have been administered have been reported, such as the recovery of acute renal failure, protein metabolism in chronic renal failure, growth improvement in uremic children, the increase in renal function in nondialyzed uremic patients, and the potential treatment of malnutrition in adult maintenance dialysis patients.
TGF-β in Renal Development and Renal Growth
Authors: Basile David P. , Hammerman Marc R.
Published: April 2003

Organogenesis of the metanephric kidney is regulated by a number of polypeptide growth factors. Members of the TGF-β family of growth factors have been shown to be produced in kidney during its development. Available evidence suggests that some of these members play key roles in metanephrogenesis by regulating the process of ureteric bud arborization. The regeneration of the S3 segment of the proximal tubule that occurs following ischemic injury recapitulates in many ways the renal developmental paradigm. The expression of TGF-β in regenerating kidney is tightly regulated postischemia. We suggest that TGF-β plays a key role in the repair process following injury and mediates some of the cellular events common to both regeneration and nephrogenesis.
TGF-β in Glomerular Disease
Authors: Shankland Stuart J. , Johnson Richard J.
Published: April 2003

Transforming growth factor-β (TGF-β) is an important cytokine in glomerular disease. Its major role may be to mediate extracellular matrix deposition, by both increasing the synthesis of matrix components and by reducing their degradation. Strong evidence supports the functional role for TGF-β in mesangial matrix expansion. However, TGF-β may also have other important functions in the glomerulus, including the regulation of cell proliferation, hypertrophy, and survival (apoptosis), as well as modulation of the local and systemic immune response.
Usefulness of Serum Pyridinoline Cross-Linked Carboxy-Terminal Telopeptides of Type I Collagen and Osteocalcin in the Study of the Bone Resorption Rate in Oophorectomized Rats
Authors: Calero Jesus A. , De la Piedra Concepcion , Díaz Curiel Manuel
Published: April 2003

The aim of this work was to determine sensitivity and specificity of serum pyridinoline cross-linked carboxy-terminal telopeptides of type I collagen (ICTP), a new biochemical marker of bone resorption, in order to study the rate of bone resorption associated with osteopenia development after oophorectomy in rats. The diagnostic accuracy of the bone formation marker osteocalcin (BGP) was also evaluated. Twelve-week-old female Wistar rats were used: (1) control group: sham-operated, treated with a placebo (n = 25); (2) OOX: oophorectomized rats treated with a placebo (n = 12), and (3) OE: oophorectomized rats treated with 17α-ethinyl estradiol 0.1 mg/kg/day for 3 months. The rats were sacrificed after treatment, and lumbar bone mineral density, BGP, and ICTP (serum assays specific for rat) were determined. As expected, OOX animals developed osteopenia. OOX rats showed a significant decrease (p < 0.05) in bone mineral density as compared with the control group, and OE rats showed no significant differences with respect to the control group. With respect to biochemical markers of bone remodeling, the OOX group showed a significant increase in BGP and ICTP (p < 0.005 and p < 0.05, respectively) with respect to control rats. However, the values of BGP and ICTP were similar in the OE group and in control animals. Areas under receiver operation characteristic curves corresponding to BGP and ICTP were 95 and 87%, respectively (p = 0.523). The results of the present work show that BGP and ICTP, the new resorption assay developed for rats, are reliable markers to be used in the study and follow-up of bone remodeling in OOX rats.
Control of Renal Function and Blood Pressure by Angiotensin II: Implications for Diabetic Glomerular Injury
Authors: Brands Michael , Granger Joey
Published: April 2003

A principal, and unique, renal effector site for angiotensin II (ANG II) is the efferent arteriole, and that has generated considerable interest regarding potential benefits of ANG II inhibition in the treatment and prevention of diabetic renal injury. A hallmark complication of long-standing diabetes is glomerular injury, and there is substantial evidence that lowering glomerular hydrostatic pressure attenuates the injury process. One way that has been accomplished is by lowering arterial pressure, but additional evidence suggests that anti-hypertensive treatment with ANG II inhibition provides even greater protection because of the associated efferent arteriolar dilation. Because of that action, ANG II inhibition in diabetes has been advocated even without diagnosis of hypertension, and the benefits of that treatment have been ascribed largely to the effect of decreased efferent arteriolar resistance to lower glomerular hydrostatic pressure. However, that renal vascular action of ANG II, together with powerful direct effects on tubular sodium reabsorption, underlie its dominant influence on chronic arterial pressure control. Moreover, the influence of ANG II on arterial pressure is not limited to hypertension; it contributes significantly to the maintenance of blood pressure when plasma ANG II levels are normal or even reduced. Thus, while acknowledging that efferent arteriolar dilation is a unique intrarenal benefit associated with ANG II inhibition, this review will focus on how and why inhibition of the multiple intrarenal actions of ANG II also protect the kidneys through systemic mechanisms, even when blood pressure and ANG II are not increased.
Hypertensive Nephropathy – An Increasing Clinical Problem
Authors: Rutkowski B. , Tylicki L. , Manitius J. , Lysiak-Szydlowska W.
Published: April 2003

Arterial hypertension-related renal damage is an increasingly common problem recently, because approximately 25% of patients currently treated with dialysis were hypertensive before renal replacement therapy was started. Hypertension is also known as a metabolic disease, while carbohydrate, purine and lipid disturbances are the features of this syndrome. On the other hand, the progression of renal disease depends on the extent of tubulointerstitial injury. For this reason, we undertook a study to evaluate the relationship between excretion of the markers of tubular damage (NAG) and some parameters of carbohydrate, purine and lipid metabolism in untreated essential hypertension. Both healthy volunteers (n = 15) aged 32.6±7.8 and essential hypertensives (n = 25) aged 37.24±11.39 underwent the same tests. These tests were performed at 2-day intervals: intravenous glucose tolerance test with 0.5 g/kg b.w. as 40% glucose solution and oral fructose load test with 1.0 g/kg b.w. Area under glucose curve (GA) and serum uric acid post-fructose (PUAA) were calculated. Fasting: insulin, total cholesterol and LDL, triglycerides, free fatty acids (FFA) and urine excretion of NAG, albumin were determined. Glomerular filtration rate was estimated as creatinine clearance. Hypertensives showed statistically higher BMI (p<0.007), NAG (p<0.02), total cholesterol (p<0.01), LDL (p<0.007), FFA (p<0.007), insulin (p<0.01), PGA (p<0.01) and PUAA (p<0.03). NAG excretion correlated positively with WHR (r = 0.40), MAP (r = 0.47) and PUAA (r = 0.47) in hypertensives only. We presume that tubular injury at an early stage of renal damage in patients with essential hypertension could be a part of metabolic syndrome X.
Uremic Toxicity: Urinary Indoxyl Sulfate is a Clinical Factor that Affects the Progression of Renal Failure
Authors: Niwa Toshimitsu , Aoyama Isao , Takayama Fumio , Tsukushi Saori , Miyazaki Takashi , Owada Akira , Shiigai Tatsuo
Published: April 2003

We recently demonstrated that indoxyl sulfate is a stimulating factor for the progression of chronic renal failure (CRF). In this study we determined whether the urine or serum levels of indoxyl sulfate are related to the progression rate of CRF in undialyzed uremic patients. Fifty-five CRF patients with a serum creatinine of >2 mg/dl who had not been treated with an oral sorbent (AST-120) were randomly enrolled in the study. We measured the serum and urine levels of indoxyl sulfate, and estimated the recent progression rate of CRF as the slope of the reciprocal serum creatinine versus time (1/S-Cr-time) plot. The mean urinary amount of indoxyl sulfate in the patients was 60 mg/day. Those with indoxyl sulfate urine levels of >60 mg/day had a significantly faster progression rate of CRF than those with <60 mg/day. Especially, those patients with indoxyl sulfate urine levels of >90 mg/day had the highest CRF progression rate and those with indoxyl sulfate urine levels of <30 mg/day had the slowest CRF progression rate. Urinary indoxyl sulfate had a significantly negative correlation with the slope of the 1/S-Cr-time plot. However, the serum level of indoxyl sulfate or the ratio of serum indoxyl sulfate to creatinine was not significantly correlated with the slope of the 1/S-Cr-time plot. In conclusion, high urine levels of indoxyl sulfate are related with a rapid progression of CRF in undialyzed uremic patients. Thus, urinary indoxyl sulfate is one of the clinical factors that affect CRF progression.
Adequate Dietary Calcium Mitigates Osteopenia Induced by Chronic Lead Exposure in Adult Rats
Authors: Gruber Helen E. , Ding Yaoxian , Stasky Audrey A. , Meyer Martha , Pandian Murugan R. , Pandian Deepa , Vaziri Nosratola D. , Grigsby Jared , Gonick Harvey C.
Published: April 2003

The purpose of the present study was to investigate bone changes in the adult rat exposed to low lead levels during intake of normal dietary calcium and to contrast these findings with data from our earlier studies performed with animals receiving low dietary calcium concurrent with lead exposure. The present study exposed adult rats to 100 ppm lead via drinking water for 12 weeks and assessed bone histology, 1,25-dihydroxyvitamin D, 25(OH)vitamin D and parathyroid hormone levels. No osteopenia was evident by quantitative bone histology, and circulating levels of 1,25-dihydroxyvitamin D, 25(OH) vitamin D and parathyroid hormone were normal. Bone ash findings documented incorporation of significant amounts of lead into bone mineral. These findings document absence of interference with vitamin D metabolism, absence of secondary hyperparathyroidism and absence of osteopenia following 12 weeks of low lead exposure in the adult rat maintained on normal calcium intake. Results stress the importance of adequate calcium intake in our elderly population who may be exposed to cumulative, low-level lead exposure.
Long-Term Results of Total Parathyroidectomy without Autotransplantation in Patients with and without Renal Failure
Authors: Hampl Hannelore , Steinmüller Thomas , Fröhling Peter , Naoum Claudia , Leder Korinna , Stabell Uwe , Schnoy Norbert , Jehle Peter M.
Published: April 2003

The optimal surgical procedure for severe renal secondary hyperparathyroidism (sHPT) is still a point of controversy. Total parathyroidectomy (PTX) without auto-transplantation was abandoned for fear of an adynamic bone condition; however, in the case of autotransplantation recurrent sHPT is frequent and promotes atherosclerosis. We studied 11 hemodialysis patients (age 59±12 years) on dialysis for 18 (12–30) years in whom total PTX was performed due to severe sHPT (group I; intact PTH: 1,240±230 pg/ml), and 5 patients (age 55±10 years) without renal insufficiency who inadvertently received total PTX during thyroid surgery (group II). After total PTX (group I, 26±18 [9–59] months; group II, 252±188 [22^480] months) both groups showed no measurable intact PTH levels. Calcium homeostasis was maintained by oral substitution with calcium (group I, calcium dialysate of 2.0 mmol/l), vitamin D and calcitriol (serum parameters in groups I and II: calcium 2.4 and 2.2 mmol/l; phosphate 1.8 and 1.1 mmol/l; 25(OH)-vitamin D3 21 and 34 ng/ml; 1,25(OH)2-vitamin D3 32 and 41 pg/ml, respectively). In group I, after total PTX there was a rapid and sustained improvement in bone pain with markedly enhanced physical activity and endurance. High turnover osteopathy markedly improved as indicated by declining levels of native osteocalcin (90±17 vs. 26±18 ng/ml), bone alkaline phosphatase (74±12 vs. 12±6 ng/ml), and carboxyterminal cross-linked telopeptide of type-I collagen (65±16 vs. 40±21 ng/ml) but increasing levels of carboxyterminal propeptide of type-I procollagen (120±36 vs. 148±41 ng/ml). Recalcification of bone was excellent as demonstrated by X-ray and confirmed by bone histology. Itching extravascular calcific deposits and calcifications of blood vessel and cardiac valves immediately stopped after total PTX. Moreover, 6 sHPT patients suffered from severe atherosclerotic lesions such as thoracic aortic aneurysm (n = 3) or abdominal aortic aneurysm (n = 3) which showed size progression before but not after total PTX when annually controlled by ultrasonography. In group II, even long after total PTX, there was no clinical, radiological, histological or biochemical evidence for low turnover osteopathy. In conclusion, our data indicate that substitution with vitamin D3 metabolites and calcium can prevent deleterious bone effects of hypoparathyroidism in hemodialysis patients and in patients with normal kidney function and may compensate for the missing PTH action. Over this, a better survival rate is expected as a consequence of the beneficial effect of total PTX on the progression of atherosclerotic lesions. We suggest reconsideration of total PTX without autotransplantation in dialysis patients with severe sHPT who are not eligible for renal transplantation.
Inflammation Nutritional State and Outcome in End Stage Renal Disease
Authors: Kaysen George
Published: April 2003

Hypoalbuminemia and reduction in lean body mass are potentially a reflection of malnutrition and portend a poor prognosis in patients with end stage renal disease (ESRD). The classic understanding of this relationship has been that ESRD patients receive insufficient dialysis, reduce dietary intake and become malnourished. Inflammation also causes many of the same changes in serum protein composition and in body morphometry as malnutrition does even with adequate calorie and protein intake. It has recently been recognized that this, the acute phase response, occurs with frequency in ESRD patients and that both the physical attributes of malnutrition and reduction in the serum concentration of albumin, transferrin, prealbumin and apolipoprotein A-I all may lack a nutritional base. The serum concentration of the acute phase proteins, C reactive protein (CRP) and serum amyloid A (SAA), as well as the cytokines orchestrating the acute phase response, predict albumin concentration as well as a number of clinically important outcomes: specifically, erythropoietin resistance rejection of renal transplant and survival. ESRD per se does not cause the acute phase response, and indeed may blunt the response to infection. Activation of the acute phase response may be a consequence of the interaction of mononuclear cells with dialysis membranes, especially cuprophane, with endotoxin in dialysate, or represents either clinically evident or obscure infection. Evaluation of the acute phase response by measurement of CRP is advisable in the evaluation of hypoalbuminemia or other stigmata of malnutrition in dialysis patients.
Unilateral Eye Closure and Interhemispheric EEG Asymmetry during Sleep in the Pigeon (Columba livia)
Authors: Rattenborg Niels C. , Amlaner Charles J. , Lima Steven L.
Published: April 2003

Aquatic mammals (i.e., Cetaceans, eared seals and manatees) and birds show interhemispheric asymmetries (IA) in slow-wave sleep-related electroencephalographic (EEG) activity, suggesting that the depth of sleep differs between hemispheres. In birds, an association between unilateral eye closure and IA has been reported in five species from three orders (i.e., Galliformes, Charadriiformes, and Anseriformes). Moreover, unilateral eye closure has been observed during behaviorally defined sleep in 29 species from 13 avian orders, suggesting that birds in general display IA during sleep. Despite the apparent prevalence of unilateral eye closure and IA in birds, previous work did not detect IA in the pigeon, thereby challenging the conclusion that this is a general feature of birds. Using digital period amplitude analysis, an objective method for quantifying EEG power (a measure of wave amplitude) across different frequencies, we demonstrate that pigeons do, in fact, display an association between unilateral eye closure and IA. For a given hemisphere, standardized 2–4 Hz EEG power was greater when the contralateral eye was closed when compared to open. We also found that pigeons used the open eye during IA to monitor their environment. In addition, individual pigeons showed a bias for keeping one eye open more than the other. The direction (left vs. right) of this bias differed across birds, and appeared to be influenced by the structure of the surrounding environment. Finally, with the addition of pigeons (order Columbiformes), IA associated with unilateral eye closure has been recorded in four avian orders, suggesting that this form of sleep is widespread in birds.
A Monte Carlo Simulation of the Influence of Sound Enamel Scattering Coefficient on Lesion Visibility in Light-Induced Fluorescence
Authors: van der Veen Monique H. , Ando Masatoshi , Stookey George K. , de Josselin de Jong Elbert
Published: April 2003

Quantitative light-induced fluorescence (QLF) is based on the dark appearance of a white spot in otherwise highly fluorescent enamel. This can be explained by the increased scattering coefficient in the white spot compared with that of sound enamel. The aim of this study was to estimate the effect of different sound enamel scattering coefficients (sSE) and enamel thickness d, caused by developmental enamel differences, on the fluorescence appearance of white-spot lesions. We ran a Monte Carlo simulation of a 4 × 4 mm2 illuminated enamel slab on a highly fluorescent background. The slab had a 0.7 × 0.7 mm2, 100-µm-deep, white spot in the center. Fluorescent and back-scattered photons re-emitted from the central 2 × 2 mm2 were recorded. We found that the fluorescence photon excitance from the white spot (FWS) was less than that of sound enamel (FSE), with an optimum difference for SSE between 20 and 80/mm. For sSE <20/mm, both FSE and FWS decreased with d. We found no relation with d for sSE >20/mm. The results indicate that for small sSE, we are suffering from edge losses, which explains why the optimum for lesion visibility is not found at sSE = 0/mm, as would be expected.