Immunophenotypic identification of acute myeloid leukemia with monocytic differentiation.
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Acute Disease↗
Biomedical subjects
R A Schultz
Publications and source records attributed to R A Schultz.
The role of fluorescence polarization immuno-assay in the diagnosis of plant-induced cardiac glycoside poisoning livestock in South Africa.
Poisoning with cardiac glycoside-containing plants is collectively the most important plant-associated poisoning of livestock in southern Africa. As a diagnosis of this significant poisoning is currently based on circumstantial evidence, a practical chemical procedure indicating the presence of cardiac glycosides in plants and animal specimens would be of considerable benefit. The fluorescence polarization immunoassay (FPIA) method, used to determine digoxin plasma levels in humans and dogs, was adapted to estimate cardiac glycoside levels in known cardiac-glycoside-containing plants as well as in the rumen and organs of dosed sheep. Positive FPIA values were obtained with bufadienolide-containing plants, while negative results were obtained with plants not known to contain cardiac glycosides. The FPIA has aided in the diagnosis of cardiac glycoside poisoning in livestock and game in 30 outbreaks examined at the Division of Toxicology, Onderstepoort Veterinary Institute. Each outbreak is briefly described. As a result of this assay, a better understanding of cardiac glycoside poisoning has been reached.
Animal Diseases↗
A study of the pathology and pathogenesis of the myocardial lesions in gousiekte, a plant-induced cardiotoxicosis of ruminants.
Myocardial lesions were studied in sheep in which gousiekte was induced by experimental dosage of Pachystigma pygmaeum, Fadogia homblei or Pavetta harborii. The single most consistent diagnostic histological feature in 33 animals was hypertrophy of myocardial fibres in the subendocardial region. Fibrosis in the subendocardial region of the apex or left ventricular wall was often scarce or absent in animals with a short latent period, and was not always prominent even in sheep with an intermediate or long latent period. The presence or absence of fibrosis cannot therefore be used to confirm or exclude gousiekte, particularly in cases with shorter latent periods. Light microscopical and ultrastructural lesions in sheep with gousiekte correspond to a large extent to changes reported in humans with dilated cardiomyopathy of unknown cause. It appears that the myocardial lesions in gousiekte represent a final common pathway of cellular damage rather than a manifestation of a specific type of heart disease. The predilection for hypertrophy of myofibres in the subendocardial region is probably related to diminished perfusion that potentiates the primary myocardial dysfunction.
Animals↗
Supernumerary tricentric derivative chromosome 15 in two boys with intractable epilepsy: another mechanism for partial hexasomy.
Rearrangements of chromosome 15q, including isodicentric 15 chromosomes and interstitial duplications and triplications, have been previously reported in association with autism spectrum disorders. We have identified two boys with exceptionally large der(15) chromosomes that are tricentric and contain four copies of the proximal long arm, including the Prader Willi/Angelman critical region, and leading to hexasomy of the involved segment. Biallelic inheritance of maternal alleles and methylation analysis indicate that the markers are maternally derived. Clinical assessment of the boys indicated severe cognitive impairment associated with marked delays in gross and fine motor skills. Social and language deficits were present in both, although the severity of the mental retardation precluded diagnosis of autism (both were considered to have pervasive developmental disorder-not otherwise specified). Neurologic manifestations included infantile spasms evolving into intractable early-onset myoclonic seizures, psychomotor regression, and profound diffuse hypotonia. These patients represent the most severe end of the spectrum of phenotypes associated with segmental aneuploidy for chromosome 15q11-q13.
Abnormalities, Multiple↗
Conditioned feed aversion as a means to prevent tulp (Homeria pallida) poisoning in cattle.
Conditioned feed aversion was investigated as a means to prevent tulp (Homeria pallida) poisoning in cattle on tulp-infested grazing. Aversion treatment with a combination of epoxyscillirosidin and lithium chloride together with a tulp-hexane extract, which served as identification factor for tulp, resulted in a significantly lower (P < 0.001) proportion of severe tulp poisoning. In a first trial where 21 averted and 21 non-averted control cattle were exposed to a tulp-infested grass pasture, only two of the averted cattle were severely poisoned compared to 13 of the non-averted control cattle. In a second trial, with cattle being exposed to a pure stand of tulp supplemented with maize residues, only two of 21 averted cattle were severely poisoned compared to 14 of 21 non-averted control cattle. Occurrence of mild tulp poisoning, however, did not differ much between averted and non-averted control cattle. The results show that conditioned feed aversion effectively restricted severe poisoning in cattle on tulp-infested grazing.
Animal Feed↗
Continuous exposure to an aversive mixture as a means of maintaining aversion to vermeerbos (Geigeria ornativa O. Hoffm.) in the presence of non-averted sheep.
Continuous exposure to an aversive mixture was investigated as a means of maintaining aversion to vermeerbos in sheep subjected to the social influence of non-averted sheep. The use of an aversive mixture was based on a hypothesis that continuous exposure to an acceptable aversive mixture (containing both the aversive substance and the identification factors of vermeerbos mixed with maize meal) would tempt sheep to consume small quantities of the aversive mixture each day and that this would keep them averted to vermeerbos, despite the social influence of non-averted sheep. Persistent aversion to a vermeerbos-maize meal mixture (1:99 by mass) by sheep continuously exposed to such an aversive mixture, after an initial aversion conditioning with lithium chloride (LiCl, 160 mg/kg BM), was demonstrated. Aversion in adjacent controls not exposed to the aversive mixture only lasted for some time. A similar result was obtained when sheep were challenged for intake of a pure stand of established vermeerbos. Three sheep continuously exposed to an aversive mixture after an initial aversion conditioning totally refused grazing the vermeerbos during a 42-day trial, despite the social influence of three non-averted control sheep grazing vermeerbos on an adjacent site. These results were confirmed by a second replication the following year. Joint grazing for an hour a day by averted and non-averted sheep during the last seven days of this replication also resulted in total avoidance of vermeerbos by the averted animals, despite continued intake of vermeerbos by the control sheep
Animal Feed↗
Cloning the human and mouse MMS19 genes and functional complementation of a yeast mms19 deletion mutant.
The MMS19 gene of the yeast Saccharomyces cerevisiae encodes a polypeptide of unknown function which is required for both nucleotide excision repair (NER) and RNA polymerase II (RNAP II) transcription. Here we report the molecular cloning of human and mouse orthologs of the yeast MMS19 gene. Both human and Drosophila MMS19 cDNAs correct thermosensitive growth and sensitivity to killing by UV radiation in a yeast mutant deleted for the MMS19 gene, indicating functional conservation between the yeast and mammalian gene products. Alignment of the translated sequences of MMS19 from multiple eukaryotes, including mouse and human, revealed the presence of several conserved regions, including a HEAT repeat domain near the C-terminus. The presence of HEAT repeats, coupled with functional complementation of yeast mutant phenotypes by the orthologous protein from higher eukaryotes, suggests a role of Mms19 protein in the assembly of a multiprotein complex(es) required for NER and RNAP II transcription. Both the mouse and human genes are ubiquitously expressed as multiple transcripts, some of which appear to derive from alternative splicing. The ratio of different transcripts varies in several different tissue types.
Alternative Splicing↗
Hyperspectral imaging: a novel approach for microscopic analysis.
BACKGROUND: The usefulness of the light microscope has been dramatically enhanced by recent developments in hardware and software. However, current technologies lack the ability to capture and analyze a high-resolution image representing a broad diversity of spectral signatures in a single-pass view. We show that hyperspectral imaging offers such a technology. METHODS AND RESULTS We developed a prototype hyperspectral imaging microscope capable of collecting the complete emission spectrum from a microscope slide. A standard epifluorescence microscope was optically coupled to an imaging spectrograph, with output recorded by a CCD camera. Software was developed for image acquisition and computer display of resultant X--Y images with spectral information. Individual images were captured representing Y-wavelength planes, with the stage successively moved in the X direction, allowing an image cube to be constructed from the compilation of generated scan files. This prototype instrument was tested with samples relevant to cytogenetic, histologic, cell fusion, microarray scanning, and materials science applications. CONCLUSIONS: Hyperspectral imaging microscopy permits the capture and identification of different spectral signatures present in an optical field during a single-pass evaluation, including molecules with overlapping but distinct emission spectra. This instrument can reduce dependence on custom optical filters and, in future imaging applications, should facilitate the use of new fluorophores or the simultaneous use of similar fluorophores.
Humans↗
Analysis of candidate genes in the CLN6 critical region using in silico cloning.
CLN6, the gene for variant late infantile neuronal ceroid lipofuscinosis, was mapped to a 4 cM region on chromosome 15q22-23. Subsequently the critical region was narrowed to less than 1 cM between microsatellite markers D15S988 and D15S1000 by additional marker typing in an expanded family resource. A physical map was constructed across this region using YAC and PAC clones and sequence was generated from two PAC clones. This sequence was analysed together with overlapping sequence generated by the Human Genome Project to identify genes within the region using an in silico cloning approach. In all, 29 genes have been identified and 18 have been analysed for mutations by direct sequencing. This powerful new approach will lead to the identification of CLN6.
Chromosome Mapping↗
Effect of pavetamine on protein synthesis in rat tissue.
Pavetamine, the active principle of plants causing gousiekte in ruminants, was found in this study to be an inhibitor of protein synthesis in the rat heart. Sprague-Dawley rats were injected intra-peritoneally with 8-10 mg/kg pavetamine and the levels of protein synthesis in different organs determined utilizing L-[4-3H]phenylalanine incorporation. In contrast to the more than 23% inhibition found in heart tissue at 4, 24 and 48 h after administration of pavetamine, the effect on the kidney, liver, spleen, intestine and skeletal muscle was minimal or returned to pretreatment levels within 48 h. These results may offer an explanation for the clinical signs observed in ruminants with gousiekte, where the heart only is affected.
Animals↗
Novel assay for Roberts syndrome assigns variable phenotypes to one complementation group.
Roberts syndrome (RS) is a rare autosomal recessive disorder characterized by heterogeneous clinical features, the most notable being tetraphocomelia, cleft lip, and cleft palate. Cells derived from most RS patients exhibit abnormal cytogenetic and cellular phenotypes that include the premature separation of para- and pericentromeric heterochromatin visible on C-banded metaphase chromosomes, a phenomenon referred to as heterochromatic splaying. Previously, it was shown that these abnormal phenotypes can be complemented following somatic cell hybridization between RS cells and control cells. In the current study, a permanent cell line was established from a new RS patient with a more severe phenotype than represented by previously established cells in culture. With a newly developed assay designed to facilitate rapid evaluation of in vitro complementation, we assigned this new patient to the same genetic complementation group defined by other, less severely affected patients. The results demonstrate that a single complementation group defines RS patients with heterochromatic splaying regardless of clinical severity.
Abnormalities, Multiple↗
The establishment of telomerase-immortalized cell lines representing human chromosome instability syndromes.
The limited life span of normal human cells represents a substantial obstacle for biochemical analysis, genetic manipulation and genetic screens. To overcome this technical barrier, immortal human cell lines are often derived from tumors or produced by transformation with viral oncogenes such as SV40 large T antigen. Cell lines produced by these approaches are invariably transformed, genomically unstable and display cellular properties that differ from their normal counterpart. It was recently shown that the ectopic expression of hTERT, encoding the catalytic subunit of human telomerase, can extend the life span of normal human cells without causing cellular transformation and genomic instability. In the present study, we have used hTERT to extend the life span of normal human skin fibroblasts derived from patients afflicted with syndromes of genomic instability and/or premature aging. Our results show that hTERT efficiently extends the life span without altering the characteristic phenotypic properties of the cells. Thus, the ectopic expression of telomerase represents a major improvement over the use of viral oncogenes for the establishment of human cell lines.
Abnormalities, Multiple↗
Cancer predisposition caused by elevated mitotic recombination in Bloom mice.
Bloom syndrome is a disorder associated with genomic instability that causes affected people to be prone to cancer. Bloom cell lines show increased sister chromatid exchange, yet are proficient in the repair of various DNA lesions. The underlying cause of this disease are mutations in a gene encoding a RECQ DNA helicase. Using embryonic stem cell technology, we have generated viable Bloom mice that are prone to a wide variety of cancers. Cell lines from these mice show elevations in the rates of mitotic recombination. We demonstrate that the increased rate of loss of heterozygosity (LOH) resulting from mitotic recombination in vivo constitutes the underlying mechanism causing tumour susceptibility in these mice.
Adenosine Triphosphatases↗
Structure of the highly conserved HERC2 gene and of multiple partially duplicated paralogs in human.
Recombination between chromosome-specific low-copy repeats (duplicons) is an underlying mechanism for several genetic disorders. Recently, a chromosome 15 duplicon was discovered in the common breakpoint regions of Prader-Willi and Angelman syndrome deletions. We identified previously the large HERC2 transcript as an ancestral gene in this duplicon, with approximately 11 HERC2-containing duplicons, and demonstrated that recessive mutations in mouse Herc2 lead to a developmental syndrome, juvenile development and fertility 2 (jdf2). We have now constructed and sequenced a genomic contig of HERC2, revealing a total of 93 exons spanning approximately 250 kb and a CpG island promoter. A processed ribosomal protein L41 pseudogene occurs in intron 2 of HERC2, and putative VNTRs occur in intron 70 (28 copies, approximately 76-bp repeat) and 3' exon 40 through intron 40 (6 copies, approximately 62-bp repeat). Sequence comparisons show that HERC2-containing duplicons have undergone several deletion, inversion, and dispersion events to form complex duplicons in 15q11, 15q13, and 16p11. To further understand the developmental role of HERC2, a highly conserved Drosophila ortholog was characterized, with 70% amino acid sequence identity to human HERC2 over the carboxy-terminal 743 residues. Combined, these studies provide significant insights into the structure of complex duplicons and into the evolutionary pathways of formation, dispersal, and genomic instability of duplicons. Our results establish that some genes not only have a protein coding function but can also play a structural role in the genome.
Amino Acid Sequence↗
Posttraumatic stress among young children after the death of a friend or acquaintance in a terrorist bombing.
The effects of traumatic loss on children who reported a friend or acquaintance killed in the 1995 Oklahoma City bombing of a federal office building were examined. Twenty-seven children who lost a friend or acquaintance and 27 demographically matched controls were assessed eight to ten months after the bombing. All but three of the children continued to experience posttraumatic stress symptoms. Those who lost a friend watched significantly more bombing-related television coverage than those without losses. Those who lost a friend had significantly more posttraumatic stress symptoms at the time of the assessment than those who lost an acquaintance. Parents and those working with children should be alert to the impact of loss even when it involves nonrelatives.
Attitude to Death↗
A krimpsiekte-like syndrome in small stock poisoned by Ornithogalum toxicarium Archer & Archer.
Krimpsiekte (the syndrome associated with chronic cardiac glycoside poisoning) was purportedly induced by Ornithlogalum toxicarium in the Karas mountains area of Keetmanshoop, Namibia. This chinkerinchee species was previously linked to a condition known as 'kwylbek' krimpsiekte in small stock in the Beaufort West district of the Western Cape Province, South Africa. In a dosing trial, respiratory distress, tachycardia and sternal recumbency were observed in 2 sheep drenched with fresh plant material. A fluorescence polarisation immunoassay (FPIA) detected the presence of a substance that cross-reacted with digoxin antibodies in some of the plant material collected at Keetmanshoop and Beaufort West. This is the first time that apparent cardiac glycoside poisoning was induced by a southern African chinkerinchee species. The presence of the cardiac glycoside-like substance in O. toxicarium requires further chemical verification.
Animals↗
Cloning, mapping and characterization of the human RAB27A gene.
Choroideremia (CHM) is an X-linked retinal degenerative disease that results from mutations in Rab Escort Protein-1 (REP1). REP1 acts in the prenylation of Rab GTPases, regulators of intracellular protein trafficking. Rab27a is unique among Rabs in that it is selectively unprenylated in CHM cells, suggesting that the degenerative process in CHM may result from unprenylation and consequent loss-of-function of Rab27a. As a first step towards the analysis of the Rab27a protein in patients, we report here the characterization of the human RAB27A gene. The putative protein encoded by this gene shares 96% identity with the previously cloned rat homologue. The RAB27A gene comprises five coding exons and two non-coding exons, of which one is alternatively used, and spans approximately 65 kb of DNA. There are three alternative poly-A addition sites in the long 3' UTR and also six potential single-nucleotide polymorphisms. The gene is located on chromosome 15q15-21.1, as determined by fluorescent in situ hybridization, and between markers D15S209 and AFM321ZD5 by radiation hybrid mapping.
3' Untranslated Regions↗
Human and mouse homologs of Escherichia coli DinB (DNA polymerase IV), members of the UmuC/DinB superfamily.
To understand the mechanisms underlying mutagenesis in eukaryotes better, we have cloned mouse and human homologs of the Escherichia coli dinB gene. E. coli dinB encodes DNA polymerase IV and greatly increases spontaneous mutations when overexpressed. The mouse and human DinB1 amino acid sequences share significant identity with E. coli DinB, including distinct motifs implicated in catalysis, suggesting conservation of the polymerase function. These proteins are members of a large superfamily of DNA damage-bypass replication proteins, including the E. coli proteins UmuC and DinB and the Saccharomyces cerevisiae proteins Rev1 and Rad30. In a phylogenetic tree, the mouse and human DinB1 proteins specifically group with E. coli DinB, suggesting a mitochondrial origin for these genes. The human DINB1 gene is localized to chromosome 5q13 and is widely expressed.
Amino Acid Sequence↗