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Biomedical subjects

R Slater

Publications and source records attributed to R Slater.

At least 37 records · Page 2Linked to original sources
PubMed1999

Secondary T-acute lymphoblastic leukaemia mimicking blast crisis in chronic myeloid leukaemia.

A 34-year-old man with chronic myeloid leukaemia (CML) firstly developed a lymphoid blast crisis of B-cell type. After a second chronic phase which lasted for > 4 years with maintenance chemotherapy of hydroxyurea, 6-mercaptopurine and methotrexate, he developed a T-cell acute lymphoblastic leukaemia of TcR-gammadelta+ type. Cytogenetic analysis revealed disappearance of the t(9;22) translocation and appearance of new abnormalities consistent with the diagnosis secondary acute leukaemia. To our knowledge, secondary leukaemia in CML has not previously been reported.

Adult↗
PubMed1999

Two-colour FISH detection of the inv(16) in interphase nuclei of patients with acute myeloid leukaemia.

The inv(16)(p13q22) and t(16;16)(p13;q22) in acute myeloid leukaemia are associated with a relatively good prognosis but are difficult to detect using classic cytogenetics. We have designed a two-colour fluorescence in situ hybridization approach that uses two DNA probes that map close to and on either side of the inv(16) p-arm breakpoint region. This new strategy clearly detected the inv(16)(p13q22)/t(16;16)(p13;q22) on both metaphase chromosomes and in interphase nuclei, even when they are of poor quality. This procedure also detected the inv(16) in cases with an additional deletion of sequences proximal to the 16p-arm breakpoint which is present in 20% of all cases.

Acute Disease↗
PubMed1999

Post-operative pain, nausea and vomiting: qualitative perspectives from telephone interviews.

Previous studies on post-operative pain, nausea and vomiting tend to be quantitative in method and focus on in-patient or day case surgery. The objectives of this study carried out in one specialist eye hospital in England were to consider post-operative pain, nausea and vomiting from a qualitative perspective. Fifty-five patients undergoing general anaesthetic short-stay ophthalmic surgery (orbital hydroxyapatite implantation) consented to participate in telephone interviews 8 days post-surgery. The interviews lasted between 20 and 60 minutes. Data were analysed thematically and offer insight into varying experiences of pain, nausea and vomiting in hospital, on discharge and at home. Results indicate that not all patients were discharged home in optimum condition. The needs of post-operative short-stay patients should come before financial imperatives to vacate beds. Patient education and information giving is discussed in the light of the findings.

Adult↗
PubMed1998

Carcinogen-induced loss of heterozygosity at the Aprt locus in somatic cells of the mouse.

Genetic events leading to the loss of heterozygosity (LOH) have been shown to play a crucial role in the development of cancer. However, LOH events do not occur only in genetically unstable cancer cells but also have been detected in normal somatic cells of mouse and man. Mice, in which one of the alleles for adenine phosphoribosyltransferase (Aprt) has been disrupted by gene targeting, were used to investigate the potency of carcinogens to induce LOH in vivo. After 7,12-dimethyl-1,2-benz[a]anthracene (DMBA) exposure, a 3-fold stronger mutagenic response was detected at the autosomal Aprt gene than at the X chromosomal hypoxantine-guanine phosphoribosyltransferase (Hprt) gene in splenic T-lymphocytes. Allele-specific PCR analysis showed that the normal, nontargeted Aprt allele was lost in 70% of the DMBA-induced Aprt mutants. Fluorescence in situ hybridization analysis demonstrated that the targeted allele had become duplicated in almost all DMBA-induced mutants that displayed LOH at Aprt. These results indicate that the main mechanisms by which DMBA caused LOH were mitotic recombination or chromosome loss and duplication but not deletion. However, after treatment with the alkylating agent N-ethyl-N-nitrosourea, Aprt had a similar mutagenic response to Hprt while the majority (90%) of N-ethyl-N-nitrosourea-induced Aprt mutants had retained both alleles. Unexpectedly, irradiation with x-rays, which induce primarily large deletions, resulted in a significant increase of the mutant frequency at Hprt but not at Aprt. This in vivo study clearly indicates that, in normal somatic cells, carcinogen exposure can result in the induction of LOH events that are compatible with cell survival and may represent an initiating event in tumorigenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1998

Determination of spontaneous loss of heterozygosity mutations in Aprt heterozygous mice.

A mouse model was generated to investigate loss of heterozygosity (LOH) events in somatic cells. The adenine phosphoribosyltransferase ( Aprt ) gene was disrupted in embryonic stem cells using a conventional gene targeting approach and subsequently Aprt hetero-zygous and homozygous mice were derived. Aprt homozygous deficient animals were viable though the mendelian inheritance pattern was skewed. On average these mice died at 6 months of age from severe renal failure. In T-lymphocytes of Aprt heterozygous mice the mean spontaneous mutant frequency at the Aprt locus was 8.7 x 10(-6) while the frequency was 0.8 x 10(-6) at the hypoxanthine phosphoribosyltransferase locus. In order to determine whether LOH events contribute to the high spontaneous mutant frequency at the Aprt locus, 140 Aprt mutant T-lymphocyte clones were expanded and analysed by allele-specific PCR. In 97 (69%) of these clones the wild-type allele had been lost. Nine of the mutant clones were characterized in more detail using dual-coloured fluorescence in situ hybridization analysis. Five out of six of the mutant clones which arose from an LOH event, based on the PCR assay, contained a duplication of the targeted allele. Therefore, mitotic recombination or chromosome loss followed by duplication of the remaining homologue appears to be the predominant mechanism for the in vivo generation of Aprt mutant T-lymphocytes.

Adenine Phosphoribosyltransferase↗
PubMed1998

Human chromosome 21 determines growth factor dependence in human/mouse B-cell hybridomas.

Interleukin 6 (IL-6) serves as a growth factor for mouse plasmacytomas. As a model for IL-6-mediated growth of plasmacytomas, we study IL-6-dependent B-cell hybridomas, which can be generated through fusion of B lymphocytes with a plasmacytoma cell line, e.g., SP2/0. In the present report, we have investigated the peculiar behavior of B-cell hybridomas with respect to IL-6 dependence. We demonstrate that although newly generated hybridomas are IL-6 dependent, many hybridomas lose this dependency at frequencies as high as 50%, shortly after fusion. We speculated that the loss of IL-6-dependent growth is due to the well-known chromosomal instability of B-cell hybridomas. Consequently, loss of IL-6 dependence is the result of loss of a specific chromosome(s). This model implies the existence of an "IL-6 dependency" gene, the loss of which makes hybridomas capable of proliferating in the absence of IL-6. Because SP2/0 is IL-6 independent, the IL-6-dependent phenotype of B-cell hybridomas, and hence the IL-6 dependency gene, must be derived from the B lymphocyte. We have tested this model by generating human/mouse B-cell hybridomas through fusion of human B lymphocytes with SP2/0. We then analyzed the human chromosome content of 10 IL-6-dependent and 14 IL-6-independent subclones. From that analysis we concluded that the presence of human chromosome 21 correlated with IL-6 dependence. This correlation was confirmed by microcell fusion experiments in which a single copy of chromosome 21 was introduced into IL-6-independent hybridomas, resulting in reconstitution of the IL-6-dependent phenotype. We therefore conclude that chromosome 21 carries an IL-6 dependency gene.

Animals↗
PubMed1998

The hydroxyapatite orbital implant: post-operative pain.

PURPOSE: To compare and quantify the degree of post-operative pain experienced by patients undergoing primary and secondary hydroxyapatite orbital implantation. METHODS: A prospective survey design was employed to monitor patients' pain pre-operatively and up to 7 days post-operatively. Fifty-five consecutive patients undergoing primary and secondary hydroxyapatite orbital implantation were recruited over a period of 1 year. Standardised anaesthetic, operative and post-operative protocols were followed. During the patients' in-patient stay nurses completed a data proforma that required them to record patients' pain using an 11-item numerical rating scale. A self-completion proforma was given to patients to score their pain at home until the first post-operative out-patient appointment. RESULTS: Patients undergoing primary implant surgery tend to experience more post-operative pain than those undergoing secondary implant surgery. A small proportion of patients experience severe post-operative pain. CONCLUSION: Post-operative pain experienced by patients undergoing primary and secondary hydroxyapatite implantation has been underestimated. This study has provided the necessary data to enable such patients to be effectively counselled pre-operatively and to plan a rational discharge policy.

Adult↗
PubMed1998

Hematological malignancies with t(9;11)(p21-22;q23)--a laboratory and clinical study of 125 cases. European 11q23 Workshop participants.

This paper reports clinical and cytogenetic data from 125 cases with t(9;11)(p21-22;q32) which were accepted for a European Union Concerted Action Workshop on 11q23. This chromosome abnormality is known to occur predominantly in acute myeloid leukemia (AML) FAB type M5a and less often in AML M4; in this series it was also found to occur, uncommonly, in other AML FAB types, in childhood acute lymphoblastic leukemia (ALL) (nine cases), in relatively young patients with myelodysplastic syndrome (MDS) (five cases), acute biphenotypic leukemia (two cases), and acute undifferentiated leukemia (one case). All age groups were represented but 50% of the patients were aged less than 15 years. The t(9;11) was the sole abnormality in 57 cases with AML; trisomy 8 was the most common additional abnormality (23 cases, including seven with further abnormalities), and 28 cases had other additional abnormalities. Among the t(9;11)+ve patients with AML, the white cell count (WBC) and age group were significant predictors of event-free survival; central nervous system (CNS) involvement or karyotype class (sole, with trisomy 8, or with other), also contributed to prognosis although our data could not show these to be independent factors. The best outcome was for patients aged 1-9 years, with low WBC, and with absence of CNS disease or presence of trisomy 8. For patients aged less than 15 years, the event-free survival for ALL patients was not significantly worse than that of AML patients.

Acute Disease↗
PubMed1998

Post-operative nausea and vomiting following orbital hydroxyapatite implant surgery.

Fifty-five consecutive patients undergoing a short-stay ophthalmic operation (orbital hydroxyapatite implantation) were recruited over 1 year to assess the frequency and duration of post-operative nausea and vomiting over 7 days. The incidence of nausea and vomiting in hospital was recorded. Patients scored their nausea and vomiting four times daily at home. By the end of the first day after surgery, 31 (75%) patients had experienced mild to severe nausea. Eighteen (38%) patients became nauseated on five or more occasions. Nineteen (35%) patients had vomited by the end of the first day after surgery and, over 7 days, 24 (43%) patients had vomited on one or more occasion. Three patients reported that they had vomited during the journey home. Vomiting was not correlated with pain or a past history of post-operative nausea and vomiting. However, there was a statistically significant correlation between nausea and pain. The high incidence of nausea and vomiting observed in this study appears to provide additional evidence of an oculo-emetic reflex. The timing of discharge and appropriate patient education are discussed.

Adult↗
PubMed1997

Cloning of cold-inducible dehydrin-like genes from the blackcurrant (Ribes nigrum L.) using RT-PCR.

A method is described for the identification of conserved genes in one plant species by using sequence information on internal motifs from well-characterized clones from another species. This sequence information is used to design primers for reverse transcriptase polymerase chain reaction (RT-PCR) and to design oligonucleotide probes to identify genuine positive amplification products. The approach was successfully used to clone cDNAs encoding cold-inducible dehydrin-like genes from the woody perennial blackcurrant, Ribes nigrum L. The strategy described can accelerate the cloning of heterologous cDNAs and is a convenient alternative to direct screening of cDNA libraries.

Amino Acid Sequence↗
PubMed1997

Assessment of chromosomal gains and losses in oral squamous cell carcinoma by comparative genomic hybridisation.

Cytogenetic studies have demonstrated that oral squamous cell carcinomas (OSCCs) are usually characterised by complex karyotypes with many marker chromosomes. We analysed the genetic changes of six OSCC cell cultures by comparative genomic hybridisation (CGH). The CGH technique provides information on chromosomal gains and losses of the whole tumour genome in a single experiment and can therefore identify regions that harbour putative tumour suppressor genes (in the case of loss of chromosomal material) or oncogenes (in the case of gain or amplification of chromosomal material). Recurrent losses were detected at chromosome arms Xp and 3p (four cases). Gains consistently occurred at chromosome arms 8q and 9q (four cases) and at 1q, 3q, 5p, 7p, and 9p (three cases). The same six tumour cultures have previously been analysed by classical karyotyping. An important discrepancy between the two techniques was the number of losses detected: 55 with karyotyping versus 26 with CGH. On the basis of the cytogenetic complexity of these tumours and on FISH experiments that confirmed the CGH results, we conclude that genetic changes, particularly losses, can be more reliably detected by CGH analysis.

Carcinoma, Squamous Cell↗
PubMed1997

Comparative genomic hybridization analysis of Wilms tumors.

In this study we have applied the technique of comparative genomic hybridization (CGH) to a large series of sporadic Wilms tumors, including six samples of the associated nephroblastomatosis. The data obtained were compared with the findings of molecular studies carried out on the same material. The aims of the study were (1) to characterize the range of genetic variation in sporadic Wilms tumor and nephroblastomatosis, (2) to determine whether changes could be found that have not been detected by commonly used techniques, and (3) to compare the sensitivity of CGH with that of conventional molecular analysis. The chromosomes that showed gains and losses by CGH were similar to those previously found in molecular and cytogenetic studies, however loss of 4q was a new event identified in 2 out of 46 tumors. We did not detect amplified genetic material. Comparison of the data from the nephroblastomatosis and tumor samples from the same patient showed that loss of 7p may be associated with malignant transformation, and that losses in 1p, 11p, 4q and gains in 1q and 12q can be early events; whilst loss in 9p and gain of 8, 10q and 18 are possible secondary changes in tumor development. The combined CGH and molecular techniques used demonstrated involvement of two specific 1p regions in the etiology of Wilms tumor.

Chromosome Aberrations↗
PubMed1996

Allelic loss of chromosome 1p as a predictor of unfavorable outcome in patients with neuroblastoma.

BACKGROUND: Neuroblastoma is a childhood tumor derived from cells of the neural crest, with a widely variable outcome. Differences in the behavior and prognosis of the tumor suggest that neuroblastoma can be divided into several biologic subgroups. We evaluated the most frequent genetic abnormalities in neuroblastoma to determine their prognostic value. METHODS: We used Southern blot analysis to study the allelic loss of chromosomes 1p, 4p, 11q, and 14q, the duplication of chromosome 17q, and the amplification of the N-myc oncogene in 89 neuroblastomas. We also determined the nuclear DNA content of the tumor cells. RESULTS: Allelic loss of chromosome 1p, N-myc amplification, and extra copies of chromosome 17q were significantly associated with unfavorable outcome. In a multivariate analysis, loss of chromosome 1p was the most powerful prognostic factor. It provided strong prognostic information when it was included in multivariate models containing the prognostic factors of age and stage or serum ferritin level and stage. Among the patients with stage I, II, or IVS disease, the mean (+/- SD) three-year event-free survival was 100 percent in those without allelic loss of chromosome 1p and 34 +/- 15 percent in those with such loss; the rates of three-year event-free survival among the patients with stage III and stage IV disease were 53 +/- 10 percent and 0 percent, respectively. CONCLUSIONS: The loss of chromosome 1p is a strong prognostic factor in patients with neuroblastoma, independently of age and stage. It reliably identifies patients at high risk in stages I, II, and IVS, which are otherwise clinically favorable. More intensive therapy may be considered in these patients. Patients in stages III and IV with allelic loss of chromosome 1p have a very poor outlook, whereas those without such loss are at moderate risk.

Blotting, Southern↗
PubMed1996

Familial sideroblastic anemia with emergence of monosomy 5 and myelodysplastic syndrome.

The case history of two sisters with pyridoxine-refractory familial sideroblastic anemia (FSA) is presented in which one developed a myelodysplastic syndrome (MDS) with monosomy for chromosome 5. Bone marrow examination of both patients at diagnosis showed erythroid hyperplasia with more than 50% ring sideroblasts. Karyotypic analysis initially showed a normal 46, XX karyotype in both of the children. Therapeutic trials with pyridoxine, prednisone, and erythropoietin were unsuccessful. The first patient required regular transfusions and developed a significant hemosiderosis. At the age of 9 years, 7.5 years after the diagnosis of FSA, refractory anemia with excess of blasts (RAEB) was diagnosed. Bone marrow cytogenetic analysis revealed a clone with monosomy for chromosome 5. Her sister's illness was detected at the age of 12 years. She has a more benign course of disease, remains largely transfusion independent and until now shows no signs of myelodysplasia. To our knowledge this is the first observation of a transition of FSA to MDS accompanied by the appearance of a chromosomal abnormality. FSA might be another type of bone marrow failure syndrome, therefore close follow-up of these patients may be necessary.

Anemia, Refractory, with Excess of Blasts↗
PubMed1996

Positional cloning of genes involved in the Beckwith-Wiedemann syndrome, hemihypertrophy, and associated childhood tumors.

The Beckwith-Wiedemann syndrome (BWS) is an overgrowth malformation syndrome that occurs with an incidence of 1:13,700 births. There is a striking incidence of childhood tumors found in BWS patients. Various lines of investigation have localized "imprinted" genes involved in BWS and associated childhood tumors to 11p15. High resolution mapping of 8 rare balanced chromosomal BWS rearrangements enabled us to identify three distinct regions on chromosome 11p15 that might harbor genes involved in the above-mentioned disorders. These results suggest genetic heterogeneity that correlates with the clinical heterogeneity seen in the patients studied. Expressed candidate gene sequences from these regions have been cloned and partly sequenced. These transcripts are either disrupted by or are at least within a few kb of these BWS chromosome breakpoints. So far, zinc-finger sequences and one Kruppel-associated box (KRAB) domain were found in independent candidate genes which are compatible with a regulating function of growth promoting genes. The abundance of expression of these genes varies from low abundant in all adult and fetal tissues tested to detectable on Northern blots of adult tissues. In addition to our 11p15 studies we have analyzed additional chromosome regions, in particular 1p. Cytogenetic, loss of heterozygosity (LOH) and comparative genomic hybridization (CGH) studies have identified 1p35 as a region of interest. A positional cloning effort to identify a balanced 1p35 translocation found in a Wilms tumor has led to the isolation of a YAC, crossing this breakpoint.

Adult↗