Mutational analysis of the hMSH2 gene reveals a three base pair deletion in a family predisposed to colorectal cancer development.
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Adult↗
Biomedical subjects
R J Scott
Publications and source records attributed to R J Scott.
Clinical heterogeneity within xeroderma pigmentosum associated with mutations in the DNA repair and transcription gene ERCC3.
The human DNA excision repair gene ERCC3 specifically corrects the nucleotide excision repair (NER) defect of xeroderma pigmentosum (XP) complementation group B. In addition to its function in NER, the ERCC3 DNA helicase was recently identified as one of the components of the human BTF2/TFIIH transcription factor complex, which is required for initiation of transcription of class II genes. To date, a single patient (XP11BE) has been assigned to this XP group B (XP-B), with ther remarkable conjunction of two autosomal recessive DNA repair deficiency disorders: XP and Cockayne syndrome (CS). The intriguing involvement of the ERCC3 protein in the vital process of transcription may provide an explanation for the rarity, severity, and wide spectrum of clinical features in this complementation group. Here we report the identification of two new XP-B patients: XPCS1BA and XPCS2BA (siblings), by microneedle injection of the cloned ERCC3 repair gene as well as by cell hybridization. Molecular analysis of the ERCC3 gene in both patients revealed a single base substitution causing a missense mutation in a region that is completely conserved in yeast, Drosophila, mouse, and human ERCC3. As in patient XP11BE, the expression of only one allele (paternal) is detected. The mutation causes a virtually complete inactivation of the NER function of the protein. Despite this severe NER defect, both patients display a late onset of neurologic impairment, mild cutaneous symptoms, and a striking absence of skin tumors even at an age of > 40 years. Analysis of the frequency of hprt- mutant T-lymphocytes in blood samples suggests a relatively low in vivo mutation frequency in these patients. Factors in addition to NER deficiency may be required for the development of cutaneous tumors.
Amino Acid Sequence↗
[Hereditary p53 mutation in a patient with multiple tumors: significance for genetic counseling].
We describe molecular genetic findings in a patient who initially presented with an intermediate teratoma of the testis and who many years later presented with an oligodendro-astrocytoma. In addition he developed a malignant histiocytoma over the scapula, an adenocarcinoma of the stomach and a late stage adenoma of the sigmoid colon. Due to the development of several neoplasms the possibility of either ataxia telangiectasia or Li-Fraumeni syndrome was considered in differential diagnosis. A molecular genetic investigation revealed that both he and his brother carried a germline p53 tumor suppressor gene mutation at codon 248. From this result we conclude that this family belongs to the Li-Fraumeni syndrome. Once characterized as belonging to the Li-Fraumeni syndrome, the remaining members of the family were typed to determine if they too carried the same mutation. The two children of the index patient were shown not to carry the mutation and are therefore at no increased risk of developing any of the Li-Fraumeni spectrum of malignancies. A molecular genetic investigation into similar families could help to prevent the development of additional malignancies as seen in the index patient, as radiotherapy may interfere with the normal function of the p53 protein and this may in turn help to orchestrate DNA repair after radiation.
Adult↗
Xeroderma pigmentosum-Cockayne syndrome complex in two patients: absence of skin tumors despite severe deficiency of DNA excision repair.
Two brothers had a complex combination of two DNA repair disorders: Cockayne syndrome and xeroderma pigmentosum. This rare combination has previously been observed in only two other patients. The clinical signs shared by these two brothers and the two other previously described patients include severe sun sensitivity, freckling, diminished stature, hearing and movement impairment, and neurologic degeneration. Although defective UV-induced unscheduled DNA synthesis has been demonstrated (5% of normal), no skin cancers have appeared in these 38- and 41-year-old brothers, whereas skin cancers developed at a relatively early age in the two previously described patients who also had defective UV-induced unscheduled DNA synthesis.
Adult↗
Familial and genetic aspects of colorectal carcinogenesis.
There is abundant clinical and pathological evidence which suggests that colorectal cancer arises in a sequential manner through a series of events that can be followed during the progression of the disease from early adenoma through to metastatic disease. The molecular events that are associated with the initiation and progression of the disease are gradually being unravelled. As the molecular characterisation of colorectal cancer continues, new mechanisms by which the disease progresses are becoming evident. In this short review, a brief description of current knowledge of colorectal cancer development is presented.
Adenomatous Polyposis Coli↗
A study of coagulase-negative staphylococci with reference to slime production, adherence, antibiotic resistance patterns and clinical significance.
Two hundred and fifty-one strains of coagulase-negative staphylococci (CNS) isolated from patients in hospital and the community were investigated for slime production and adherence as indicators of pathogenicity. Staphylococcus epidermidis formed 68.5% (126) of the isolates of CNS from blood and central venous catheter (CVC) tips, of which 46.0% (58) were slime-positive and adherent. Clinically significant infections were associated with 55.2% (32) of the slime-positive adherent strains isolated and 11.1% (four) of slime-negative non-adherent strains of S. epidermidis. For other species of CNS isolated from blood and CVC tips 74.1% (43) were slime negative non-adherent and 18.6% (eight) of these were considered clinically significant isolates while none of the slime positive adherent strains were associated with a clinically significant infection. Slime production and adherence were not characteristic properties of CNS causing community-acquired urinary tract infection or colonizing the nasal mucosa. It is concluded that slime production and adherence had a limited role in the differentiation between clinically significant and contaminant strains isolated from blood cultures; however, the absence of slime and adherence in isolates of S. epidermidis suggested a lack of pathogenicity.
Bacterial Adhesion↗
Fatal perinatal nephropathy with onset in intrauterine life.
A girl, born at 29 weeks' gestation, died of renal failure aged 16 days. Postmortem histology showed diffuse mesangial sclerosis with failure of development of the cortex. This is an unusual cause of neonatal renal failure, and it demonstrates the effect of disease arising in utero and influencing the development of the kidney.
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A comparison of immunohistochemical markers of cell proliferation with experimentally determined growth fraction.
The relationship between immunoreactivity for cell proliferation markers (Ki67 and PCNA) and the growth fraction as determined by the fraction of labelled mitoses method was assessed in xenograft tumours grown from the LoVo cell line in nude mice. FLM curves were constructed by injecting tritiated thymidine and then preparing autoradiographs from the tumours. From this data an estimate of growth fraction and cell cycle time were made. Using frozen material from the same tumours, the Ki67 index was determined by immunostaining. PCNA staining was determined in the fixed material which had been used for the autoradiographs. The results show that Ki67 staining follows the same trend as the FLM-determined growth fraction as the tumour increases in size and the rate of growth decreases. However the Ki67 index does produce a consistent overestimate of the growth fraction in this in-vivo system, as compared to observations in cell culture. PCNA staining showed virtually 100 per cent positive staining in all the tumours, which is likely to reflect the long half-life of the antigen, compared to the very fast cell-cycle time of the xenograft tumours. These results show that staining with proliferation markers is not a precise determinant of growth fraction. Ki67 staining is a method that can be usefully applied as an operational marker of cell proliferation, but should not be used uncritically. Further caution is necessary in the use of PCNA. The findings also demonstrate the need to use a range of methods when assessing a new proliferation marker.
Animals↗
A Brassica napus mRNA expressed specifically in developing microspores.
The I3 cDNA isolated from a library made from 2-4 mm (immature) anthers of Brassica napus shows microspore-specific expression. Homologous transcripts are detected in buds and anthers of male-fertile plants, but not in green tissues, roots, or in cytoplasmic male-sterile buds. High expression of the transcript is limited to microspores entering and undergoing mitosis. The predicted peptide sequence of the cDNA shows an unusual repeated alanine/proline motif at the C-terminus, which may be of importance in the native protein structure.
Amino Acid Sequence↗
Changes in the expression of class I major histocompatibility complex antigen RNA induced by interferon in rat hepatoma cells.
The rat hepatoma cell line 17X was studied to determine if it expressed major histocompatibility complex (MHC) class I antigen RNA and to see if interferon treatment would affect its expression. Under normal cell culture conditions, MHC class I RNA in 17X hepatoma cells is virtually undetectable. Administration of rat interferon at a concentration of 1000 units/ml for 48 h to 17X cells in culture resulted in the appearance of detectable levels of RNA for MHC class I antigens. The interferon-induced increase in class I RNA was accompanied by de novo synthesis of immunoprecipitable, metabolically radiolabeled class I antigens in the 17X hepatoma cells.
Animals↗
Change in the ploidy state of rat liver cells during chemical hepatocarcinogenesis and its relationship to the increased expression of alpha-fetoprotein.
The DNA content and ploidy state of cells isolated from the livers of rats exposed to the carcinogen 3'-methyl-4-dimethylaminoazobenzene for 10 and 20 weeks, as determined by flow cytometry, were correlated with the development of oval cells in the livers of treated animals and with serum levels of the oncoprotein alpha-fetoprotein (AFP). The study revealed that there was initially a steady rise in the AFP levels found in the carcinogen treated rats. Associated with this increase was a change in the ploidy pattern of the liver from an approximately equal mixture of tetraploid and diploid cells to a predominantly diploid state. Histologically, there was an increase in the number of oval cells during carcinogen treatment, and when stained immunohistochemically for AFP, these cells were positive. We conclude that the changing state of the diploid and tetraploid cell populations is due to the proliferation of oval cells and that these cells are responsible for the initial increase of serum AFP. The maintenance of the diploid population of cells at later periods of the study is a reflection of the persistence of a new cell type, possibly derived from oval cells. The effect of 3'-methyl-4-dimethylaminoazobenzene was not reversed if the animals were withdrawn from the diet at 10 weeks. In addition, in the cases of hepatocellular carcinoma that were found, a population of cells was detected by flow cytometry that contained altered DNA.
Animals↗
Non-traumatic cerebrospinal-fluid rhinorrhoea in cases of primary empty-sella syndrome.
Non-traumatic cerebrospinal-fluid rhinorrhoea is a rare condition. Its insidious onset may occur with a sneezing or coughing episode which may lead to an incorrect diagnosis of allergic rhinitis or vasomotor rhinorrhoea. Two cases that occurred in association with primary empty-sella syndrome are described--in the second case, the fistula arose from the pituitary fossa. The history, incidence, clinical profile, investigation and management of this condition are reviewed.
Adult↗
Fatal thermal injury.
Two fatal cases of thermal injury are described, one of which was the result of heat stroke and the other was the result of the uncommon condition, neuroleptic malignant syndrome. The clinical profiles, management and post-mortem findings of these two separate conditions are compared to highlight their important differences.
Aged↗
A community outbreak of group A beta haemolytic streptococci with transferable resistance to erythromycin.
Erythromycin resistance amongst group A streptococci (GAS) in Great Britain is a relatively rare occurrence and outbreaks have been sporadically reported. Over an 8-month period in 1986 ten associated cases occurred in the town of Bridgewater in Somerset. Isolates were group A, type M4 and resistant to erythromycin (MIC 8 mg/l) but sensitive to lincomycin and clindamycin. Erythromycin resistance was transferable from all isolates to a group A recipient strain. No plasmid DNA could be detected in the original isolates or transconjugants.
Adult↗
A new comprehensive anaesthetic record.
Eternal vigilance and strict attention to detail are the 'sine qua non' of safe anaesthesia with the contemporaneous anaesthetic record being the documentation. As an alternative to the manifold and often inadequate forms currently in use, a new rapidly completed anaesthetic record incorporating a comprehensive checklist is presented. Guidelines of the Faculty of Anaesthetists, Royal Australasian College of Surgeons are met. It is argued that the chart improves safety not only by its direction to attention during the peroperative visit and equipment check, but also by its demand for the ongoing attention of the anaesthetist. Reservations are expressed about 'black box' recording by trend printout and a perspective for computerised and automated anaesthetic records is also discussed.
Anesthesia Recovery Period↗
Pyruvate kinase isoenzyme transitions in cultures of fetal rat hepatocytes.
Changes in the expression of two isoenzymic forms of pyruvate kinase in fetal hepatocyte cultures derived from 15- and 19-day gestation rats are studied by immunocytochemical localization of the respective antigens. Initially, in cultures established from 15-day gestation rats only the 'embryonic' form of the enzyme (M2-PK) is detected in all cells. Cells which stain positively for the liver specific form of the enzyme (L-PK) are not observed. After 2 days' culture, a significant number of cells have become positive for L-PK. All the positive cells have a morphology which is typical of liver parenchymal cells. However, the majority of parenchymal cells remain negative for L-PK while retaining M2-PK. In contrast, all cells which display a fibroblastic morphology, as well as clear epithelial cells are M2-PK positive, but L-PK negative. In 5-day-old cultures, all hepatocytes have become L-PK positive. Hepatocytes derived from 19-day gestation rat liver stain positively for L-PK on day 1 of culture in agreement with previously published biochemical data. A minor population of negative cells is non-parenchymal in appearance. All parenchymal cells are negative when the culture is stained with M2-PK specific antibody. Five days after the culture is established, many non-parenchymal cells are present. Such cells are L-PK negative and M2-PK positive and their presence in cultures derived from both 15- and 19-day gestation rats explains the persistence of M2-PK. This study reveals that during enzymic differentiation of fetal hepatocytes, all immature hepatocytes are initially capable of expressing M2-PK while they do not produce L-PK. During culture, a sub-population of these cells initiates synthesis of L-PK, indicating that only a fraction of the cells differentiate. At the same time, hepatocytes which do not stain for M2-PK appear, which suggests that cells which initiate L-PK synthesis have ceased to make M2-PK. Eventually all hepatocytes are L-PK positive and M2-PK negative, indicating that a switchover in expression of the pyruvate kinase isoenzymes has occurred.
Animals↗
Carriage of Neisseria meningitidis: investigations in a military establishment.
A prevalence study of personnel on a Royal Naval Air Station revealed that 23.0% of 2479 personnel were carrying a meningococcus. Selected groups of personnel were subsequently swabbed monthly for a year. We have shown that it is only by repeated swabbing and the use of optimal methods including enrichment media that one can have a hope of identifying the 'true' carriage rate. A presumed virulent strain of Neisseria meningitidis B15 P1.16 was repeatedly isolated from three personnel who remained well, as did their colleagues both at their work place and socially. The study served to emphasize our lack of knowledge of the virulence factors associated with N. meningitidis.
Adult↗
Sodium-hydrogen ion exchange in rabbit renal cortical slices incubated in acetate media.
1. Thin slices (0.2-0.3 mm) of rabbit renal cortex have been incubated in isosmotic oxygenated acetate media at 25 degrees C with or without ouabain (10(-3) M), amiloride (2 x 10(-3) M) or iodoacetamide (10(-3) M). 2. Slices in normal isosmotic 146 mM-sodium-132 mM-acetate media swelled as reported previously (Cooke & Macknight, 1984). This swelling was not prevented by amiloride or by metabolic inhibition. 3. Slices in isosmotic 132 mM-choline-132 mM-acetate media gained much less water and were little affected by ouabain, amiloride or metabolic inhibition. Choline was able to substitute neither for sodium nor for potassium in activating preparations of renal cortical Na+-K+-ATPase in chloride or in acetate media. 4. Slices in isosmotic 20 mM-sodium-132 mM-acetate medium swelled nearly as much as did slices in normal sodium acetate medium. However, this swelling was impaired markedly by amiloride, by ouabain and by metabolic inhibition. 5. There was a direct correlation between medium sodium concentration and slice water content as sodium was increased from 1.25 to 30 mM in 132 mM-acetate media. However, up to a sodium concentration of 10 mM, amiloride (2 x 10(-3) M) completely prevented this increase in water content. 6. Increasing medium amiloride concentration from 10(-5) to 10(-3) M progressively inhibited cellular swelling in 10 mM-sodium-132 mM-acetate medium. It is concluded that, under these experimental conditions, the dominant pathway for hydrogen ion extrusion from the cells was via amiloride-sensitive sodium-hydrogen exchange. 7. The results are discussed in terms of a model which explains cellular swelling in acetate media in terms of (a) non-ionic diffusion of acetic acid across plasma membranes impermeable to the acetate anion, (b) removal from the cells of the hydrogen ion gained with the acetate by amiloride-sensitive sodium-hydrogen counter-transport and (c) subsequent extrusion of sodium from the cell accompanied by potassium uptake via the ouabain-sensitive Na+-K+-ATPase. 8. The results provide evidence for ion movements across the luminal plasma membrane of proximal tubular cells in rabbit renal cortical slices.
Acetates↗