Biomedical subjects
Publications and source records attributed to A Slavotinek.
We report a 6 year old child with a small de novo interstitial deletion of proximal 4q, karyotype 46,XX,del(4)(pter-->q12::q13.1-->qter). She has made good developmental progress and attends normal school with minimal assistance. We review published reports and clinical findings in patients with proximal 4q deletions.
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In this report, in situ hybridization with whole chromosome painting probes was used to paint radiation-induced micronuclei (MN) in three lymphoblastoid cells lines to investigate the frequency of radiation-induced MN. The results obtained for four different chromosomes showed that there was a significant deviation of the numbers of signal-positive MN from that expected on the basis of DNA proportionality. Restriction of the analysis to three chromosomes showed that the deviations arose primarily from chromosome 7, which was underrepresented in the numbers of signal-positive MN in the group of chromosomes studied.
We report three babies with malformations of left-right asymmetry who were born to mothers with insulin-dependent diabetes mellitus. One infant had left isomerism and asplenia, one had polysplenia, and the third baby had situs inversus with a neural tube defect. Defects of left-right asymmetry have not previously been well recognized as part of the spectrum of anomalies associated with maternal diabetes. We believe that the association of maternal diabetes with these malformations in the infants is not coincidental, and that diabetes mellitus has an aetiological role in this spectrum of abnormalities. Two of the mothers had elevated HbA1C levels in pregnancy, and thus the malformations may be due to poor glycaemic control, although other teratogenic mechanisms associated with diabetes cannot be excluded. Finally, to our knowledge, the finding of left isomerism with asplenia (part of the spectrum of right isomerism) is rare. The occurrence of both forms of isomerism in different parts of the same body supports the model of random development of laterality following the interruption of normal developmental processes.
Anthracenyl-amino acid/dipeptides are novel topoisomerase (topo) inhibitors which can be actively cytotoxic in the low microM range. The present studies have been performed to determine whether cells treated with the topo II catalytic inhibitor NU/ICRF 500 (serine derivative) would manifest cytogenetic lesions consistent with its proposed mechanism of enzyme inhibition. Three other compounds were included for comparison: NU/ICRF 505 (tyrosine) which stabilises topo I cleavable complexes, NU/ICRF 602 (gly-gly) a non-cytotoxic catalytic inhibitor of topo I and II and NU/ICRF 502 (alanine) a non-cytotoxic non-topo inhibitor. Chromosomal damage was measured using the micronucleus test. NU/ICRF 500 (7.5-30 microM) induced an increase in CREST negative micronuclei (11-15 per 500 cells) in human lymphocytes (HL) and blocked the traverse of HL through the cell cycle, with cells accumulating in G2/M at 15 microM drug and G1/S at 30 microM drug. NU/ICRF 502 was without effect in the micronucleus test. NU/ICRF 500 and 602 (90-150 microM) caused no block in passage of synchronised metaphase Chinese hamster ovary cells through mitosis whereas NU/ICRF 505 produced a significant delay. DNA measurements of post-mitotic cells revealed that after NU/ICRF 500 treatment nuclei had a 4C DNA content, indicative of a lack of chromosomal segregation. Normal (2C) DNA content was observed with NU/ICRF 505 and 602. Overall, the data for NU/ICRF 500 are consistent with the cytogenetic modifications expected after catalytic inhibition of topo II and suggest that cell death may be mediated, at least in part, through this mechanism.
In these experiments, the cytokinesis-block technique was used to measure the spontaneous and radiation-induced micronucleus frequencies in lymphoblastoid cell lines from normal individuals and individuals with radiation-sensitive syndromes. The radiation-induced micronucleus frequencies were measured at different harvest times to investigate the optimum time to measure radiation-induced cytogenetic damage with the cytokinesis-block technique. The frequency of radiation-induced micronuclei was found to be independent of the frequency of binucleate cells in these cell lines. Longer incubation times were complicated by increasing numbers of mononucleate and multinucleate cells, and scoring slides at an early incubation time after the maximum frequency of binucleate cells is reached was recommended. Two of the cell lines (one established from an individual with ataxia telangiectasia, and one from an infant with mitotic instability) had significantly higher radiation-induced micronucleus frequencies than the control cell lines. Finally, the radiation-induced micronucleus frequencies in three of the cell lines were measured by flow cytometry, and the results ranked the cell lines in the same order of radiosensitivity as the cytokinesis block technique.
There is increasing interest in the development of rapid assays of radiosensitivity which can be used on clinical specimens. Unfortunately, the measurement of radiation survival using clonogenic assays, which are the established standard, can be difficult and time consuming. We have used the MTT assay to measure the radiation survival of four lymphoblastoid cell lines with low plating efficiencies. We measured surviving fractions both when the irradiated cells had regained exponential growth and when the non-irradiated cells had undergone four or more doublings. The results were compared to surviving fractions measured by clonogenic assay. We found both methods could be used successfully to rank the cell lines in order of radiosensitivity. However, cells exposed to the higher radiation doses in the MTT assay did not always regain exponential growth, limiting the dose range for which the assay was useful. We also found the best correlation between the two assays was sometimes obtained by using the MTT surviving fractions from different days for different radiation dose levels. Thus, although the MTT assay can be used to measure radiation survival in relation to other cell lines, its use can be complicated by restrictions on radiation dose ranges and difficulties with data interpretation.
We used an intracellular zinc-specific fluorophore, Zinquin, in conjunction with fluorescence video image analysis, to reveal labile zinc in pancreatic islet cells, which concentrate this metal for use in synthesis, storage, and secretion of insulin. Zinquin vividly demonstrated zinc in the islet cell secretory granules, which formed a brightly labeled crescent in the cytoplasm between one side of the nucleus and the plasma membrane. Lower but still appreciable amounts of zinc were detected in the remaining cytoplasm, but there was little labeling in the nucleus. Fluorescence intensity varied among islet cells, suggesting differences in zinc content. Their average fluorescence intensity greatly surpassed that of the surrounding pancreatic acinar cells in frozen sections of pancreas and in all other types of cell studied, including lymphocytes, neutrophils, fibroblasts, and erythrocytes. Less labile zinc was detected in cells of the mouse insulinoma cell line NIT-1, regardless of whether they were maintained in long-term culture in the presence or absence of exogenous extracellular zinc. Exposure of islet or insulinoma cells to a high concentration of glucose or other secretagogue decreased the content of labile zinc. Zinquin should be a useful probe for revealing changes in zinc homeostasis in islet B-cells that may be important in their dysfunction and death during diabetes.
It has been suggested that the enzyme topoisomerase II may be important in chromosome segregation due to the role played by the enzyme in decatenating the intertwined DNA molecules that result from DNA replication. Inhibition of the enzyme has been found by some workers to inhibit chromatid separation in mammalian cells, while others have reported that the passage of cells through mitosis is unaffected. Inhibition of the enzyme with topoisomerase II inhibiting drugs also results in the formation of micronuclei as a consequence of DNA damage. We have used the micronucleus assay with CREST staining to investigate whether the micronuclei formed in neonatal lymphocytes after inhibition of topoisomerase II are formed from whole chromosomes, implying non-disjunction, or acentric fragments. We found that treatment with both amasacrine and etoposide caused a dose-related increase in the number of CREST negative micronuclei, with only a very small increase in the number of CREST positive micronuclei at high concentrations of the compounds. Although we cannot conclude from our experiments that treatment with topoisomerase II inhibitors does not affect the segregation of neonatal lymphocytes, the production of CREST negative micronuclei suggests that segregation abnormalities are less important than other mechanisms which may cause cytotoxicity from exposure to these compounds.
We scored the frequency of micronuclei in bone-marrow erythroblasts from 41 patients with childhood acute lymphoblastic leukaemia (childhood ALL) at diagnosis and during their 2-year treatment cycle in order to see whether there would be any variation in the cytogenetic damage induced by chemotherapy. We found that most patients showed the same trend in micronucleus frequency, with a progressive rise from the diagnostic slide through induction to pre-intensification and completion of treatment. The rise was attributed to damage to the erythroblasts occurring as a result of chemotherapy, and was judged not prognostically significant in this study.
The relationship between the formation of micronuclei (MN) following the treatment of cell lines with ionizing radiation and the radiation survival of cell lines is important as the MN assay has the potential to predict radiation survival. Studies investigating the relationship have reached conflicting conclusions. We examined the relationship between MN formation and radiation survival measured by a clonogenic assay in six lymphoblastoid cell lines over a dose range of 0-2.0 Gy. We did not find a predictive relationship between the radiation induced MN frequency and the radiation survival in these cell lines. Possible reasons for the lack of correlation include variations in the percentage of scorable cells after irradiation and culture with cytochalasin B, different numbers of cells in the G1 phase of the cell cycle at the time of irradiation, a greater toleration of the loss of MN by hyperdiploid cell lines compared to diploid cell lines and quantitative differences in the conversion of chromosomal fragments into MN for the cell lines.
As part of the Adelaide Obesity Surgery Study, we have reviewed all patients who have undergone revisional surgery. Of the 31 0 trial patients, 63 (20%) had revisions 1-69 (median 32) months following their original surgery-30% of all 105 gastrogastrostomy (GG) operations, 22% of 106 gastroplasty (GP) procedures, and 9% of 99 gastric bypasses (GB). Failure was due to stomal dilatation, 11% of all trial patients (71% of GG revisions), stomal stenosis, 6% (52% of GP revisions) and staple dehiscence, 4%. There was no mortality and a low hospital morbidity. Long-term success was only 23% (follow-up at least 3 years) and was achieved at considerable expense (3 reversals, 10 further revisions, 44 endoscopic procedures). Revisional surgery was successful in 45% of patients with stomal dilatation or dehiscence but in only 17% with stenosis. Overall, the most successful operation was revision of, or conversion to, gastric bypass (58% success rate), compared with gastroplasty (24%) and gastrogastrostomy (25%). Our long-term results following revisional surgery were disappointing, particularly for stenosis, and most failures followed revision to GG or GP. Roux-en-Y gastric bypass is the procedure of choice when considering revision.
This study was undertaken to determine whether psychosocial factors determined during a pre-operative semi-structured psychiatric interview were associated either with the amount of weight loss following obesity surgery or with dropping out from follow-up after surgery. Multiple regression and discriminant function analysis of weight loss at six, twelve, twenty four and thirty six months showed no correlation between psychosocial variables and the amount of weight lost or with dropping out from follow-up. It is concluded that the type of psychiatric interview performed in this study does not yield information which reliably predicts weight loss after surgery for obesity.
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An 11-year-old girl was diagnosed as having ectodermal dysplasia, with abnormalities of her nails, teeth, and hair noted from infancy. Her hair was unruly and investigations confirmed the changes seen in "cheveux incoiffables"-the uncombable hair syndrome. She also had atopy requiring treatment to control asthma and eczema. When she was 8 years old she developed vulval lichen sclerosus, which was controlled easily with early treatment. The coexistence of these conditions is discussed.